Advancing Breast Cancer Risk Assessment among White and Black Women Using Artificial Intelligence and Sequential Mammograms
Principal Investigator: Aimilia Gastounioti, PhD Goal: Our goal is to discover novel imaging phenotypes of breast cancer risk from mammography and bring effective personalized breast cancer risk models to more racially diverse screening populations. Description: This is a study to learn whether a woman’s risk of developing breast cancer can be predicted by using computers to evaluate changes in her mammograms over time. Breast cancer risk is related to several factors, including having family members with breast cancer, certain changes in genes (mutations), and reproductive history (like number of children and breastfeeding history). Some previous studies have shown that a woman’s risk is associated with what her mammogram looks like when analyzed by a computer – looking at features of the image before a cancer is visible. However, most of these mammograms were from White women, and it is not known whether these same features can predict breast cancer risk in Black women. Because Black women are affected by more aggressive cancers that show up at younger ages, it would be particularly helpful to be able to predict breast cancer risk in this group of women. The previous studies have also looked only at features from a single mammogram. This study will look at changes in mammograms from year to year to find out whether risk can be better predicted from these changes. We will retrospectively analyze mammograms of both White and Black women in order to develop a computer program that will give a more accurate estimate of each woman’s individual risk of breast cancer, regardless of race. The ultimate goal is to improve our use of screening mammograms and lower risk of dying from breast cancer.
Early Phase I Window of Opportunity Trial of Pyrimethamine as an Inhibitor of NRF2 in HPV-negative Head and Neck Squamous Cell Carcinoma
Principal Investigator: Ben Major, PhD Goal: Test the pyrimenthamine drug as an inhibitor of the NRF2 protein in head and neck squamous cell carcinoma, which if proven true could result in the ability to sensitize NRF2-active cancers to standard of care chemotherapy, radiation therapy, and immune inhibition therapy. Description: Patients suffering advanced head and neck squamous cell carcinoma (HNSCC) face poor prognoses and limited treatment options. Massive DNA sequencing efforts have revealed genes, that when mutated, contribute to HNSCC progression and resistance to chemotherapy and radiation therapy. Principle among these is the NRF2 gene, which for decades has been known to protect normal cells from stress and environmental toxins like air pollution and sun exposure. The evolution of a normal cell to a cancer cell is exceedingly stressful to cellular life, and as such, mutation and activation of NRF2 provides the growing cancer with critical survival capabilities. Moreover, HNSCC cancers with NRF2 mutations and activation have been shown to be resistant to front line chemotherapy, radiation therapy and immune-directed therapy. In this study of HNSCC patients with advanced disease, we will determine if Pyrimethamine treatment for two weeks results in loss of activity of DHFR and NRF2. If proven true, these data will support a near-future Phase 2 clinical study wherein we test whether Pyrimethamine sensitizes NRF2-active cancers to standard of care chemotherapy, radiation therapy, and immune inhibition therapy.
Principal Investigator: Ting Wang, PhD Goal: Exploring Precision Oncology Opportunities Contributed by Transposable Elements Description: We recently discovered that the drug Pyrimethamine has an inhibitory effect on NRF2 activity in cell culture models and in mouse models. Mechanistically, we found that Pyrimethamine inhibits the dihydrofolate reductase (DHFR) enzyme, and that this results in inhibition of NRF2. Pyrimethamine is an FDA approved drug that has been used for decades for treatment of protozoan infections and malaria. A growing body of research shows that it has potential antitumor activity, however it has not been previously studied in HNSCC or specifically in the context of NRF2-active tumors.
Principal Investigator: Jason Held, PhD Goal: Address critical knowledge gaps in our functional and mechanistic understanding of how silencing the enzyme GSTP1 re-wires cysteine oxidation of the proteome in breast cancer, hopefully providing new ways to inhibit breast cancer growth and transformation. Description: Glutathione S-transferase Pi 1 (GSTP1) is an enzyme that we find is uniquely and dramatically downregulated in luminal and some Her2-positive breast cancers, as well as liver and prostate cancers. This proposal will investigate how GSTP1 acts as a tumor suppressor via regulation of cysteine oxidation in proteins. This is a novel function for GTP1, so we will characterize its structure and role in cancer signaling.
Next Generation Theranostic 89Zr/227Th-conjugated PSMA Inhibitor for Precision Molecular Imaging and Radiotherapy of Metastatic of Prostate Cancer
Principal Investigator: Hanwen Zhang, PhD Goal: Advance a next generation theranostic pair with a novel compound, 89Zr/227Th-Lumi-PSMAUrea, for targeting imaging and alpha particle therapy of metastatic prostate cancer. Description: Prostate cancer (PCa) is the most common non-cutaneous malignancy diagnosed in men and is their second leading cause of cancer death. Over 90 percent of these cancer cells overexpress a cell-surface protein, prostate specific membrane antigen (PSMA). Radiopharmaceuticals that target PSMA can be used to sensitively detect and characterize PCa, as well as direct cancer-specific radiation to sites throughout the body. The FDA has recently approved several PSMA-agents for imaging and targeted therapy. However, the overall survival extension of Lutetium-177 labeled therapeutics is only four months, due to the low absorbed dose at sites of disease from this low energy beta particle emitter. By developing a next generation theranostic pair with a novel compound, 89Zr/227Th-Lumi-PSMAUrea, which enables sensitive and high contrast PET imaging with 89Zr and exquisitely potent high-absorbed dose alpha particle therapy with 227Th, we seek to generate further safety and efficacy data in order to translate 89Zr-Lumi-PSMAUrea for first-in-man studies. 89Zr-Lumi-PSMAUrea PET imaging will precisely guide and predict 227Th-Lumi-PSMAUrea therapy to eradicate prostate malignancy.
Phase I Dose Escalation and Dose Expansion Study of Duvelisib Following Chimeric Antigen Receptor T Cell Therapy
Principal Investigator: Armin Ghobadi, MD Goal: Our goal is to determine if adding the targeted oral drug duvelisib to standard treatment with genetically modified immune cells (chimeric antigen receptor or “CAR” T cells) will decrease cellular immunotherapy-related side effects and help CAR T cells to more effectively kill non-Hodgkin lymphoma. Description: Non-Hodgkin lymphoma is the most common blood cancer in adults. It develops from the lymphatic glands, which form an important part of the immune system. Currently, the first treatment patients receive for this cancer is high doses of chemotherapy, which can cure about half of patients. However, if the lymphoma does not disappear after chemotherapy or comes back after treatment, additional chemotherapy treatments are unlikely to provide a cure. Physicians are increasingly interested in harnessing the body’s own immune system to help fight cancer, including lymphoma. One promising approach is the collection and modification of the patient’s own immune cells to make a special type of anti-cancer treatment called chimeric antigen receptor T cells or “CAR T cells”. These cells are specifically designed to find and destroy lymphoma cells after recognizing a specific protein on their surface. In prior studies, the use of CAR T cells has been shown to cure about a third of patients with NHL who were not cured by chemotherapy. Unfortunately, this therapy can have significant side effects that require hospitalization or admission to the intensive care unit, including fevers, confusion, difficulty breathing and low blood pressure. Further, the majority of patients are still not cured by this approach and most treatments are ineffective if the lymphoma comes back after receiving CAR T cell therapy. Consequently, our study proposes to use duvelisib, a medicine that can be taken by mouth, to improve the function of CAR T cells during treatment. Based on work in the laboratory, we believe it will decrease the side effects of CAR T cell treatment while helping CAR T cells to last longer and kill cancer cells better. With this approach, we hope to increase the number of patients who can safely receive CAR T cells and provide better control of the cancer, ultimately leading to more patients with lymphoma being cured.
Phase I trial of CA-4948 in Combination with FOLFOX/PD-1 Inhibitor +/- Trastuzumab for Untreated Unresectable Gastric and Esophageal Cancer
Principal Investigator: Kian-Huat Lim, MD, PhD Goal: Our goal is to improve the efficacy of treatment for patients with metastatic gastric and esophageal cancers by combining a new drug called CA-4948 with current chemo-immunotherapy treatments to activate killer T cells. Description: Chronic inflammation is an important risk factor that leads to the development of gastrointestinal cancers including gastric, esophageal, pancreatic, and colon cancers. Under the microscope, we can easily observe that these cancers are heavily surrounded by inflammatory cells. These inflammatory cells secrete soluble factors that not only fuel cancer cell growth, but also block our bodies’ main immune defense mechanism, particularly the killer T cells. We have recently identified IRAK4, an enzyme within cancer cells, as a key target that drives chronic inflammation in gastrointestinal cancers. We found that blocking IRAK4 using a new drug called CA-4948 can dramatically decrease inflammatory cells inside the cancer of experimental mouse models, causing the killer T cells to be partly activated. When we added an immunotherapy agent called anti-PD1 antibody, we observed a further boost in killer T cell activity and number, which led to complete elimination of cancers in more than half of the experimental mice. This is an exciting finding that led us to open a new clinical trial for patients with metastatic gastric and esophageal cancers, in which chemotherapy and immunotherapy are already part of the regimen. Our hope is that adding CA-4948 will make these therapies more effective and last longer in patients. To our best knowledge, this is the first clinical trial that combines CA-4948 with chemo-immunotherapy in cancer patients. If shown to be effective from this study, we will proceed to open this clinical trial in a larger scale in collaboration with other cancer centers in the future.
Principal Investigator: Roberto Galletto, PhD Goal: Define the role of Pif1 in telomere maintenance in cancer cells and to identify small molecule inhibitors to test the functional outcome of Pif1 inhibition. Description: One hallmark of cancer cells is their ability to maintain the ends of their chromosomes, in a special DNA structure called telomeres. This gives cancer cells the ability to replicate indefinitely. In general, telomere maintenance in cancer cells occurs via reactivation of a protein called telomerase, a specialized enzyme that extends the DNA length of telomeres. However, in about 10-15 percent of tumors, telomeres are maintained by a telomerase-independent pathway, termed Alternative Lengthening of Telomeres (ALT).
Principal Investigator: Elizabeth Salerno, PhD, MPH Goal: Determine the feasibility and preliminary efficacy of a physical therapist-delivered prehabilitation physical activity intervention to prevent cognitive decline in breast cancer patients undergoing chemotherapy, hopefully leading to a significant paradigm shift in the way we implement standard of care rehabilitation during cancer survivorship. Description: Despite chemotherapy’s effectiveness at treating breast cancer, many patients experience severe declines in cognitive function during treatment that can persist for years. Our team’s previous research suggests that regular physical activity may help, but randomized controlled trials are necessary to confirm these findings. Our research also suggests that physical activity should begin as soon as possible after a cancer diagnosis, but most targeted physical activity interventions are designed to begin after chemotherapy completion, once cognition has already declined. Interventions delivered before or during treatment (e.g., prehabilitation) may be better suited to prevent treatment-related impairments and improve prognosis; however, these trials are difficult in practice. Oncologists have limited (if any) time to systematically advise patients on physical activity behavior, and patients are overwhelmed by a new cancer diagnosis and hesitant to begin activity on their own without proper support. Ideal models of cancer care should be pragmatic, which includes referral to physical activity programs through existing healthcare pathways to support enrollment, adherence, and long-term behavioral maintenance. To address these gaps, we propose to conduct a pilot randomized controlled trial exploring both the preliminary efficacy and feasibility of a remote, physical therapist-delivered prehabilitation physical activity intervention to prevent cognitive decline in breast cancer patients undergoing chemotherapy, compared with a wait-list control condition. Findings from this study will provide critical preliminary data for scaling our intervention to confirm the role of physical activity on cognitive function and implement pragmatic approaches to prehabilitation during treatment for breast cancer.
Principal Investigator: Sheila Stewart, PhD Goal: Our goal is to develop smarter breast cancer therapies that have a more potent effect at limiting disease progression by interrogating how age-related changes in non-tumor cells contribute to increases in breast cancer. Description: As neither normal cells nor majority of tumors rely on ALT, specific inhibition of this pathway provides an attractive target for therapeutic intervention specifically tailored to ALT+ cancers. However, the mechanisms of ALT in human tumors and suitable targets for small molecule inhibition have remained elusive. To this end, we identify human Pif1, an enzyme that unwinds the DNA double helix and facilitates DNA replication at hard-to-replicate sites, as a candidate to be targeted for inhibition in ALT.
Principal Investigator: Patricia Ribeiro Pereira, PhD Goal: Our goal is to enhance the efficacy of immunotherapy treatments in gastric tumors. We aim to use molecular imaging techniques to investigate the mechanisms of cancer-cell surface protein regulation to enhance immune checkpoint blockade efficacy in gastric tumors. Description: Cancer cells can become invisible to monoclonal antibody drugs (i.e., a form of immunotherapy) by decreasing the availability of cancer-cell surface proteins, which are the ones targeted by these drugs. We have recently shown that proteins present in high quantities in gastric cancer cells are not always available at the cell surface for the effective binding of antibody drugs. The processes by which proteins are distributed throughout the cancer cell and internalized from the cell membrane could explain why immunotherapies only work in 30% of patients with gastric cancer. Thus, there is a critical need to understand the biological mechanisms of cancer-cell surface protein regulation and develop approaches that allow effective control of these processes. The Disease Imaging and Therapy lab uses cutting-edge imaging technologies to visualize in the whole body and in real-time the biological processes by which proteins are internalized into the gastric cancer cell and away from the membrane where antibody drugs bind to them. We then develop pharmacologic approaches to control these processes in ways that enable the conversion of non-responder gastric cancers into responders. This proposal aims to use our imaging methodologies to discover the membrane trafficking mechanisms of PD-L1—an important membrane protein that prevents immune cells from destroying cancer cells—and determine whether PD-L1 trafficking can be modulated to enhance the efficacy of antibody drugs targeting PD-L1 in gastric cancers. These approaches will enhance antibody therapies targeting cell-surface receptors and increase the number of patients that benefit from them.
Principal Investigator: Chris Maher, PhD Goal: Understand how our recently discovered lncRNA, RAMS11, interacts with a pioneering transcription factor to promote tumor growth and metastasis in non-small cell lung cancer patients. Description: Lung cancer is the most common malignancy and has the highest mortality worldwide, with approximately 80-85 percent of all lung cancer patients categorized as being non-small cell lung cancer (NSCLC). Despite improvements in diagnosis and treatment options, currently only five percent of NSCLC patients with aggressive disease survive five years or longer. This represents an unmet clinical need to improve the current treatments. To address this, NSCLC research has primarily focused on understanding which genes that produce proteins, also known as protein-coding genes, have altered activity in tumor cells compared to normal cells. However, our lab recently discovered a novel class of genes that eluded researchers because, contrary to central dogma, they enable a cell to function without generating a protein (we refer to as long non-coding RNA [lncRNA] genes). Building on this discovery, our lab is focusing on how these understudied lncRNA genes enable a lung tumor to develop and eventually spread throughout the body (also known as metastases). More specifically, we recently discovered a lncRNA that becomes more active in lung cancer patients that have more aggressive disease. The current proposal will study how this lncRNA acts as a “master regulator” by interacting with specific proteins to alter their normal function and cause the original tumor to grow and spread. In the longer-term we intend to “drug” this lncRNA, ultimately leading to the development of novel therapeutics for improving outcomes in this deadly disease.
Evaluation of Single Fraction Accelerated Partial Breast Irradiation vs. Five Fraction Accelerated Partial Breast Irradiation for Low-risk Stage 0 and I Breast Carcinoma
Principal Investigator: Imran Zoberi, MD Goal: To reduce the number of required post-lumpectomy radiation treatments for breast cancer patients by determining whether just one treatment of Accelerated Partial Breast Irradiation is as safe and effective as the five-treatment standard of care Description: Women with small breast cancers often are treated with a surgery called a lumpectomy. This surgery removes the breast cancer and a small amount of surrounding normal breast tissue. Some of these women also are treated with radiation therapy. This is given after a lumpectomy to lower the chance of the breast cancer coming back. This treatment has been performed since the 1980s and involves X-ray treatments to the entire breast, given once a day for several weeks. Trials done in the early 2000s on women with small breast cancers have proved that radiation therapy does not need to be given to the entire breast. This type of radiation therapy is called Accelerated Partial Breast Irradiation, or APBI. Later trials have shown that APBI can be given using X-rays for five treatments, which is the current standard of care for APBI at Siteman. There is another method of APBI that gives a single radiation treatment immediately after a lumpectomy in the operating room. This is called intraoperative APBI. Washington University radiation oncologists at Siteman liked the idea of one radiation treatment but were not comfortable giving this radiation therapy without knowing all the details of an individual patient’s breast cancer. Instead, in 2014, they did a trial of a single APBI treatment given in a regular radiation room a few weeks after surgery in patients whose cancer had been completely removed with spread of cancer to lymph nodes. Fifty women participated in that trial, and there were no troublesome side effects from the treatment. The current proposed trial continues to study single APBI treatment by testing it against the five-treatment standard of care. The trial is open to breast cancer patients who are postmenopausal and who have small cancers that have not spread to lymph nodes. These patients will either get one or five ABPI radiation treatments. We will check on all participating patients for five years to see if one group does better. Our hope and expectation is that both groups do well. If breast cancer patients could be treated with just one radiation treatment that is safe and effective, it would be great news for this large group of patients.
Principal Investigator: Jaebok Choi, PhD, MA Goal: To determine how a certain protein, PKN1, in a bone marrow donor’s immune cells causes graft-versus-host disease, and how inactivating this protein would allow the healthy immune cells to attack the patient’s leukemia cells but not healthy organs Description: The most effective treatment for many patients with leukemia or other blood cancers is to administer bone marrow transplants containing immune cells obtained from a healthy donor. Although these cells can effectively kill the patient’s cancerous cells, in about 50% of patients the donor cells begin to attack the patient’s skin, intestines and liver in a phenomenon known as graft-versus-host disease, or GvHD. GvHD can be severely debilitating or even fatal and is the primary obstacle to successful transplantation. We have identified one protein in the donor immune cells that causes GvHD in mice. Pharmacologically inactivating this protein, named protein kinase N1, or PKN1, an enzyme controlling cellular signaling, eliminates GvHD, yet the healthy immune cells can still kill the patient’s leukemia cells. In this proposal, we will determine how this protein causes GvHD. This will have a major impact in the development of new therapeutic strategies to provide an inexpensive, safe and effective way of overcoming the barriers to successful transplantation and will permit the routine use of bone marrow transplantation in patients who may not have suitable donors to improve outcomes.
Principal Investigators: Matthew Ciorba, MD, (pictured) and Jonathan Mitchem, MD, in a collaboration with the University of Missouri in Columbia Goal: To identify new personalized therapeutic approaches for rectal cancer that increase cancer-free survival and reduce treatment-related side effects Description: Rectal cancer affects more than 40,000 people in the U.S. each year. At the time of diagnosis, most of these cancers have spread beyond the wall of the rectum into nearby tissues or to nearby lymph nodes. This spread necessitates a combined approach to treatment, including chemotherapy, radiation and surgery. Despite this aggressive approach, nearly half of patients have their cancer return within five years and, unfortunately, these therapies have significant negative side effects. Therefore, there is an important need to identify new therapeutic approaches for rectal cancer that increase cancer-free survival and reduce treatment related side effects. Researchers at Siteman Cancer Center and Ellis Fischel Cancer Center at the University of Columbia have formed a team to address this need. Ciorba, a gastroenterologist, and Mitchem, a colorectal surgeon, will use state-of-the art techniques for analyzing gene expression within tumors, to identify how immune cells present in a tumor at diagnosis can be used to identify patients most likely to benefit from aggressive therapy. Additionally, this work will look to identify new pathways to target for future rectal cancer therapies. To take the next step in testing the new therapy, the research team will use patient-derived biopsies to build a “living biobank” of cancer and immune cells for use on new targets identified. In summary, using cutting-edge techniques for data acquisition and analysis, along with building a testing platform using human samples, this project will establish a precision medicine pipeline to facilitate identifying new personalized approaches to treating patients with rectal cancer.
Principal Investigator: Daniel Link, MD Goal: To test the therapeutic activity of drugs targeting the ATR gene in combination with drugs that inhibit DNA replication in TP53-mutated acute myeloid leukemia Description: Acute myeloid leukemia (AML) with mutations in the TP53 gene represents approximately 10% of cases and carries a dismal prognosis. Indeed, there is no effective treatment and median survival is less than 6 months. Accordingly, there is a pressing unmet clinical need for better therapies for these patients. We have early evidence suggesting that TP53-mutated AML is especially sensitive to drugs that inhibit the ATR gene, especially when combined with drugs that inhibit DNA replication (the process by which DNA makes a copy of itself). Here, we will rigorously test the ability of such drug combinations to kill TP53-mutated AML in the laboratory. Importantly, drugs that inhibit ATR and DNA replication are already being used in the clinic (although not together). Thus, if successful, this research could rapidly lead to a clinical trial of this novel drug combination for patients in this very high-risk group of AML with limited treatment options.
Principal Investigator: Russell Pachynski, MD Goal: To explore how the protein chemerin works to treat prostate cancer that has spread into the bones, and to develop this into a treatment that can be used in the clinic Description: The body’s immune system is able to control the growth of cancers, and the goal of cancer immune-based therapy, or immunotherapy, is to favorably alter the immune response in order to shrink the cancer. Unfortunately, tumors are able to evade or escape the immune system response through a number of means. We recently discovered that one way in which tumors can escape the immune system is by turning off a protein called chemerin in the tumor. Chemerin normally helps direct immune cells to go into the tumors from the blood. We have found in models of prostate and other cancers, such as breast cancer and melanoma, that if we increase the amount of chemerin in the tumors we can increase the number of immune cells that are able to get into the tumors. This results in significant shrinkage of the cancer. Our proposed studies here will look at using chemerin to treat prostate cancer that has spread into the bones, which is commonly seen in men with prostate cancer. We will test chemerin alone and combine it with some other immunotherapies that can help the immune cells become more active against the cancer cells. We have also developed a new immunotherapy based on chemerin. This immunotherapy can be targeted to any tumor type, though we will initially target prostate cancer, and has the potential to improve immune responses and help shrink tumors anywhere in the body. Increasing the number of immune cells in tumors using this new immunotherapy could potentially improve immune responses in those tumors where there are not many immune cells in the tumors, such as prostate, breast and pancreatic cancers, and this could be used alone or in combination with existing immunotherapies.
A Multi-Modal Single-Cell Approach to Developing Personalized Combinatorial Treatments for Glioblastoma
Principal Investigator: Allegra Petti, PhD, BA Goal: To identify and isolate the distinct cell populations that comprise individual glioblastoma tumors, test the drug sensitivities of each cell population, and identify effective drug combinations tailored to the unique composition of each tumor Description: Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is a devastating disease. Treatment for GBM has evolved little in recent decades, probably because this tumor type is notoriously complex. Each GBM tumor is heterogeneous with respect to genetics, tumor cell state and immune microenvironment. In particular, a new technique called single-cell RNA-sequencing (scRNA-seq) has revealed that each GBM is a mixture of different types of tumor cells, each with different biological properties. Consequently, each tumor is essentially multiple diseases, and it will probably be necessary to treat each patient with drug combinations targeted to that individual’s tumor. Although scRNA-seq has enabled us to understand the complexity of GBM, it has not yet helped us treat the disease. This is partly because it is difficult to physically isolate and study the cell types discovered using scRNA-seq. Here, we propose a novel approach to isolating these GBM tumor cell populations, studying their therapeutic vulnerabilities and identifying personalized drug combinations that target multiple cell populations simultaneously. Our approach is based on a new technology called CITE-seq, an extension of scRNA-seq that will enable us to define tumor cell populations and isolate them using a technique called flow sorting. We will test the drug sensitivities of each cell population, then identify combinations of drugs that more effectively eradicate the tumor. Our long-term goal is to adapt this approach to the clinic, so we can readily identify drug combinations for any individual’s tumor.
Understanding Transcriptional and Epigenetic Regulation of Metastasis and Treatment Response in Head and Neck Cancer
Principal Investigator: Sidharth Puram, MD, PhD Goal: To identify new therapies for head and neck cancers that may prevent metastasis and avoid mechanisms of treatment resistance Description: Head and neck tumors are composed of cells that are not all the same but instead have different functions, much like bees in a hive. The diversity of bees makes it hard for a single insecticide to kill the hive; the queen bee may be hiding deep within the hive far away from the insecticide while worker bees may leave the hive altogether. We are interested in identifying new therapies for head and neck cancer that might prevent “worker bee” cells from leaving the hive while dynamically responding to mechanisms of treatment resistance, much like bees in the hive avoid insecticide. In particular, we are interested in improving a new class of drugs called epigenetic therapies by better understanding how these inhibitors work using head and neck cancer models. Our prior data suggests some cancer cells may change their shape and ability to invade, which we call a “transitional” state. We believe that epigenetic inhibitors may control this “transitional” program or direct other pathways we have not yet discovered. By understanding how current epigenetic therapies work, we can design a super-insecticide that may be more effective against all the bees in the hive by improving upon the specificity and reliability of existing inhibitors. Our ultimate goal is to develop new, more dynamic treatments for head and neck cancer that may prevent invasion and metastasis while more robustly avoiding mechanisms of treatment resistance.
Principal Investigator: Jieya Shao, PhD Goal: To understand how pSer784-VCP, a DNA repair protein, is naturally degraded in cells, and whether such a process can be manipulated to compromise DNA repair and increase cancer chemotherapy response Description: Although recent years have seen the development of new cancer therapies targeting specific cancer drivers or boosting patient immunities, chemotherapies continue to be the mainstay treatment for patients with triple-negative breast cancer and other cancers for which no easily targetable cancer drivers are available or no clinical benefits are yet achievable through immunotherapies. In fact, our ability to use chemotherapies to treat cancer has improved significantly over the past several years, owing to the development of new drugs with better safety profiles that are more toxic to the tumor cells than the healthy cells. This is best exemplified by the PARP inhibitors, which have received FDA approval to treat multiple cancer types such as breast, ovarian and pancreatic cancer. PARP inhibitors work by causing DNA damage because PARP is a highly important DNA repair protein. In certain tumor cells, such as those harboring BRCA1/2 mutations, DNA repair machineries are defective. Consequently, they are more prone to death when PARP is inhibited compared to healthy cells whose DNA repair machineries are intact. Although PARP inhibitors were originally approved to treat BRCA1/2-mutant tumors, we now know they also are effective for tumors without BRCA1/2 mutations but that are harboring other DNA repair defects. Identifying such DNA repair defects, or findings ways to induce them, can broaden the utility of PARP inhibitors and expand their clinical benefits to more cancer patients. In this study, we focus on a highly important DNA repair protein named pSer784-VCP that drives cellular resistance to different chemotherapy agents including PARP inhibitors based on our recent clinical and experimental investigations. The goal of this study is to understand how pSer784-VCP is naturally degraded in cells and whether such a process can be manipulated to compromise DNA repair and increase cancer chemotherapy response.
Characterizing cancer cell intrinsic and immunologic phenotypes of estrogen receptor positive and HER2 negative breast cancer resistant to endocrine therapy and CDK4/6 inhibitor
Principal investigator: Cynthia Ma, MD, PhD Goal: To develop biomarkers that predict a patient’s response to CDK4/6 inhibitors, the newest drugs available in the clinic for patients with stage IV estrogen receptor positive and HER2 negative (ER+/HER2-) disease, and to identify drug targets in resistant tumors, to design better treatments for breast cancer patients Description: Estrogen receptor positive (ER+)/HER2 negative (HER2-) breast cancer (BC) represents more than 70% of breast cancer diagnosis and contributes to the majority of breast cancer deaths. Despite curative intent local and systemic treatments, up to 30% of patients who initially presented with early stage disease (localized to the breast and lymph nodes) will experience disease spread to distant organs (metastatic or stage IV) in the years to come. Cyclin-dependent-kinase (CDK) 4/6 inhibitors (CDK4/6i) are the newest drugs available in the clinic for patients with stage IV disease. However, up to 15% to 30% of patients do not benefit from these drugs. In addition, administrating a CDK4/6i in patients with early stage disease has not consistently shown to reduce recurrence. There is an unmet need for biomarkers that identify which patient will respond to CDK4/6i and to develop effective treatments for patients with resistant tumors. In this proposal, we plan to perform in-depth molecular analysis of tumor biopsies collected from patients with locally advanced ER+/HER2- BC enrolled in the ongoing investigator initiated trial NeoPalAna (neoadjuvant palbociclib and anastrozole) that tests the efficacy of the CDK4/6i palbocilcib. The goal is to develop biomarkers that predict response to CDK4/6i and to identify drug targets in resistant tumors. We will perform tumor DNA and RNA sequencing as well as single cell proteomics using the state-of-the-art multi-plex immunofluorescent (MxIF) approach to interrogate the molecular characteristics of both tumor cells and immune cells in the tumor microenvironment. We expect to generate data needed to develop new diagnostic and treatment strategies for patients with ER+/HER2- BC.
Principal investigator: Foluso Ademuyiwa, MD, MPH, MSCI Goal: To test if using an African American facilitator who performs a rapid genetic risk assessment screening on African American women with breast cancer is feasible in the clinic setting, to improve the rates of provider recommendations for genetic counseling and testing and ultimately improve medical care for African American women with breast cancer Description: Women carrying a BRCA mutation have a high risk of developing breast cancer. Genetic counseling and testing identifies high-risk individuals before breast cancer develops, allowing for personalized screening, preventive surgeries or medications to reduce risks. For those already diagnosed, identifying these genes leads to different treatment options. African Americans account for less than 5% of people who get testing for BRCA mutations and other breast cancer risk genes. Less than 60% of African Americans with breast cancer who ought to have testing for genetic mutations actually receive testing as part of their medical care. Studies show that medical providers have lower referral rates for African Americans, and are much more likely to refer Whites with breast cancer for genetic counseling and testing. Therefore, providers play a significant role in worsening racial disparities in the use of genetic services for African Americans with breast cancer. Our goal is to test if using an African American facilitator who performs a rapid genetic risk assessment screening on African American women with breast cancer is feasible in the clinic setting. We will also identify reasons why medical providers have lower rates of recommending genetic counseling and testing for African Americans, and investigate what information African American patients with breast cancer want to get from their medical providers about genetic counseling and testing. Our long-term plan is to improve the rates of provider recommendations for genetic counseling and testing and ultimately improve medical care for African Americans with breast cancer.
Principal investigator: Taeho Kim, PhD Goal: To take the lessons learned, tools and models available from MR-guided radiotherapy, an expensive tool that requires expertise not found in most clinics, and apply them to the more common X-ray guided radiotherapy to achieve effective treatment of pancreatic cancer in the standard clinic Description: In 2019, pancreatic cancer was the ninth most common form of cancer in the United States but caused the second greatest number of cancer-related deaths. This disease is so deadly because it is often found at a late stage. Radiation therapy is effective at treating pancreatic cancer but difficult to deliver because the pancreas is surrounded by healthy organs very sensitive to radiation. Radiation therapy in combination with magnetic resonance imaging to guide the radiation (MRgRT) has proven to be one of the best tools to combat pancreatic cancer. However, MRgRT is very expensive and requires expertise not found in most clinics, but the more common X-ray guided radiotherapy (XgRT) cannot currently achieve the same success as MRgRT. The major goal of this project is to take the lessons learned, tools and models available from MRgRT and apply them to XgRT to achieve effective treatment of pancreatic cancer in the standard clinic. To do this we propose measuring tumor motion from high-speed MRI movies (cine MRI) and applying this information to tumor outlines on X-ray images used in XgRT. We will take advantage of a library of previously acquired pancreatic cancer images from clinical MRgRT and CT systems that is unique to our institution. Combining the benefits of MRgRT with conventional XgRT will enable a low cost but highly effective solution for pancreatic cancer treatment. This project can maximize the benefits of XgRT by taking advantage of the synergy brought by the combination of MRI for accurate tumor localization, respiratory motion management for comprehensive tumor motion control, and X-ray imaging-guided radiotherapy for rapid delivery.
Identification of ubiquitin ligases and substrates specifically interacting with a new pancreatic cancer suppressor ABTB2
Principal investigators: Guangfu Li, PhD, and David DeNardo, PhD, in collaboration with the University of Missouri in Columbia Goal: To further test the therapeutic efficacy of ABTB2-expressing virus in clinically relevant KPC mice and patient-derived xenograft mice toward the ultimate clinical trial in patients with pancreatic cancer and identify ABTB2-specific interacting partner protein for developing novel targeted therapies for pancreatic cancer Description: Pancreatic cancer (PaC) is one of the most lethal human malignancies and the fourth leading cause of cancer-related death without effective treatment. Conventional therapeutic options, including surgery, chemotherapy and radiation therapy provide very limited benefit to human patients. The development of a new, efficient therapeutic approach for PaC is urgently required. We have identified such a new target for PaC. We have found that a gene called ABTB2 has a strong effect in suppressing PaC growth. We have constructed a therapeutic virus to infect PaC cells and manipulate ABTB2 expression, and found that this can significantly induce suppression of PaC growth without detectable adverse effects. We propose to further test the therapeutic efficacy of ABTB2-containing virus in two additional models of PaC and identify the pathways that mediate ABTB2’s function. The generated data will help us select patients for an ABTB2-targeted therapy and advance our agent towards clinical testing.
Predicting head and neck cancer outcomes using partial epithelial-to-mesenchymal transition biomarker
Principal investigator: Angela Mazul, PhD, MPH Goal: To develop a reliable genomic test to guide treatment decision-making in oral cavity cancer patients across diverse socioeconomic and demographic groups Description: The anatomy of the oral cavity is complex, with features necessary to speech and eating. Thus, treating oral cavity cancer must be carefully balanced between cancer outcomes – such as recurrence and survivorship – and quality of life – such as speech, swallow and taste. At the same time, there are severe racial and socioeconomic disparities in cancer outcomes. Black oral cavity patients have worse survival and receive lower quality treatment than White patients, even when considering socioeconomic status. Thus, there is a critical need to develop a reliable genomic test to guide treatment decision-making in oral cavity cancer patients across diverse socioeconomic and demographic groups. We developed a biomarker using RNA genetic material from oral cavity tumors. This biomarker predicts which cancers are more aggressive, as well as poor cancer outcomes. Early data also suggest the biomarker may also capture racial disparities and differences. Our study aims to further develop our innovative biomarker in a diverse cohort constructed from oral cavity patients treated at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. Additionally, we will study how this biomarker interacts with race and socioeconomic status. This line of research will help us understand the relationship between our oral cavity biomarker, race, socioeconomic status and cancer outcomes. These results will advance precision medicine for oral cavity cancer by challenging current approaches by integrating genomics with socioeconomic status.
Principal investigators: Jose Zevallos, MD, MPH, and Jin Zhang, PhD Goal: To understand both how and why “high-risk HPV genomic structures” may be a useful biomarker of high-risk disease for HPV-associated oropharyngeal cancer and ultimately better identify the high versus low risk patients at the time of diagnosis Description: Human papillomavirus (HPV) is a common viral infection which can cause a number of cancers including oropharyngeal squamous cell carcinoma (OPSCC). The rate of HPV-associated OPSCC is rising in the United States and abroad. Using next-generation sequencing technology, our laboratory has recently identified specific features of HPV within tumor cells that are associated with significantly lower overall survival. We call these “high-risk HPV genomic structures” (HRGS). This is important because 4 of 5 patients with HPV-associated OPSCC survive their disease, but it is difficult to predict in advance of treatment who is likely to survive or fail treatment. We believe our findings could represent an important biomarker of high-risk disease, which would allow us to better identify the high versus low risk patients at the time of diagnosis. The work proposed in this grant will accomplish two tasks. First, we will advance HRGS toward use as a cancer biomarker by creating and testing a computer program which will detect HRGS from highly complex datasets. We will determine how much better we can identify high versus low risk disease compared to our existing methods, which mainly use gross measures of how advanced the disease is at time of diagnosis. We will also perform experiments which evaluate a potential mechanism which would explain why patients with HRGS have worse outcomes. The results of this work will help us better understand both how and why HRGS may be a useful biomarker of high-risk disease for HPV-associated oropharyngeal cancer.
Washington University Glioblastoma Team Science: An integrated and collaborative approach to develop new therapies for glioblastoma
Principal investigators: Milan Chheda, MD (principal investigator); Michael Diamond, MD, PhD; Tanner Johanns, MD, PhD; Gavin Dunn, MD, PhD; Kenneth Murphy, MD, PhD; Allegra Petti, PhD; Hong Chen, PhD; Albert Kim, MD, PhD; Robyn Klein, MD, PhD; Jian Campian, MD, PhD; Erik Herzog, PhD; Joshua Rubin, MD, PhD; and Jingqin (Rosy) Luo, PhD Goal: To develop new ways to treat patients with glioblastoma based on discoveries made at Washington University in St. Louis Description: The long-term goal of this proposal is to develop treatments that will become the new standard of care for patients with glioblastoma (GBM). The Washington University GBM Team Science group represents seven departments at Washington University, including both the Medical and Arts and Sciences campuses and clinicians who treat adults and children. These physicians and scientists have complementary expertise in cancer therapeutics, immunology, clinical trial design, circadian biology, pathology and engineering and all are singularly focused on developing innovative ways to treat and cure GBM. GBM kills most adults within two years. Despite surgery, radiation and temozolomide chemotherapy, most GBMs recur within 6 months. There is no standard of care for recurrent GBM. Recurrence and treatment resistance is driven, in part, by the existence of cancer stem cells, poor anti-tumor immunological response, non-optimal dosing of chemotherapy and inadequate penetration of drugs across the blood-brain barrier and throughout the tumor. This pre-SPORE proposal will address each of these barriers. In project 1, the team will develop zika virus as a new therapy for GBM. In project 2, they are developing ways to engage an underappreciated immune cell to launch a better anti-tumor defense. In project 3, they will develop new understanding on how laser and ultrasound treatment of tumors increases delivery of chemotherapy and may be combined with other treatments. In project 4, they pursue exciting findings that circadian rhythms may make a major difference in how patients respond to treatment.
Principal Investigator: David DeNardo, PhD and William Hawkins, MD Goal: To test whether a novel combination therapy in PDAC patients will prime the patient’s immune system to attack cancer cells and drive tumor protective immunity during and after pancreas cancer surgery Description: Pancreas cancer is a devastating diagnosis with a <10% five-year survival rate. Attempts to employ immunotherapy in pancreas cancer have not achieved significant clinical benefits. This is likely due to the profoundly immune suppressive environment in which the pancreas tumors grow. Our group has found a way to prime the immune system to attack the cancer even in its hostile home environment. We have done so by targeting one immune cell type, called dendritic cells. Dendritic cells act as field generals for the immune system, directing and coordinated attacks on cancer. Unfortunately, patients with pancreatic cancer systemically lack this critical cell type. We have discovered a therapeutic combination witch restores dendritic cell number both systemically and with pancreas tumors. We have observed in animal models, that this strategy results in coordinated immune attacks on the cancer cell and disease control. We now seek to employ this strategy in human pancreatic ductal adenocarcinoma (PDAC) patients, by treating them with a combination of FLT3L and CD40-agonists therapeutics. These are the agents that we have shown can drive dendritic cells to coordinate immune attack on the tumor, and our belief is this will drive tumor protective immunity during and after pancreas cancer surgery.
Phase II Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate Uproleselan (GMI-1271) for GI Toxicity Prophylaxis during Melphalan-Conditioned Autologous Hematopoietic Cell Transplantation
Principal Investigator:Geoffrey Uy, MD Goal: To test if the drug uproleselan can reduce the severity of injury to the GI tract and lessen GI symptoms for multiple myeloma patients following chemotherapy Description: Injury to the mucosal lining of the gastrointestinal (GI) tract, also known as mucositis, is a major complication of chemotherapy resulting in pain, nausea, and diarrhea. Mucositis also places patients at increased risk for infection, malnutrition, prolonged hospital stays and can limit the ability to tolerate further treatment for their cancer. In this study, we are testing if a medicine, uproleselan, can reduce the severity of mucositis and GI symptoms after chemotherapy. Uproleselan blocks a molecule called E-selectin which is important in how white blood cells travel to the GI tract after injury from chemotherapy. We will be conducting the study in patients with multiple myeloma who are receiving high dose chemotherapy followed by an autologous hematopoietic cell transplant. While autologous transplants are very effective at treating multiple myeloma, the treatment is associated with high rates of severe GI toxicity from mucositis.
Principal Investigator: Sergej Djuranovic, PhD Goal: To understand how gene regulation and protein production is altered in cancer cells by dissecting the importance of specific RNA motifs in the ZCRB1 gene, a gene which is known to further control the production of cancer-related genes Description: Protein production by the ribosome is central to life and disease. Information embedded within DNA is copied into messenger RNA (mRNA) which is subsequently translated into protein. Ribosomes, a complex molecular machine found in all living cells, are the sites of protein translation. Ribosomal stalling and frameshifting are control mechanisms that occur during protein production in cells. The direct consequence of ribosome stalling and frameshifting is lower levels of protein production and production of shorter and non-functional protein forms in cells. Recently, we discovered that the presence of certain RNA motifs (polyA tracks) in mRNA sequences induces ribosomes to stall and misread the encoded information. Abnormal forms and levels of a particular protein may negatively impact health of the cell and therefore lead to cancer. Our goal is to dissect the importance of polyA tracks in the ZCRB1 gene, a gene which further controls production of multiple cancer related genes. The knowledge that we gain will broaden our understanding of how gene regulation and protein production is altered in cancer.
Principal Investigator: Ryan Fields, MD and Chris Maher, PhD Goal: To study how a particular molecule from a newly discovered class of molecules (called lncRNAs) acts to alter normal cell function promotes colorectal cancer metastasis chemotherapy resistance Description: Colorectal cancer (CRC) is the most common gastrointestinal cancer in the US with approximately 50% of patients developing advanced disease, of which greater than 80% die within 5-years. This represents an unmet clinical need to improve the current inadequate treatments. Currently our limited understanding of the ways in which the original colon tumor spreads throughout the body (also known as metastases) is a critical barrier for improved treatment. We discovered a new class of molecules involved in metastasis called lncRNAs. Based on our preliminary data, we will study a promising lncRNA that acts as a “master regulator” by interacting with specific proteins to alter their normal function, cause tumor spread/metastases, and promote chemotherapy resistance. In the longer-term we intend to “drug” this lncRNA, ultimately leading to the development of novel therapeutics for improving outcomes in this deadly disease.
Developing an Academic and Community Practice Collaborative Care Model for Metastatic Breast Cancer Care
Principal Investigator: Ashley J. Housten, OTD, MSCI Goal: To implement and evaluate a coordinated care model for metastatic breast cancer patients in the St. Louis region to improve collaboration between academic and community oncology practices Description: Meeting the needs of patients with metastatic breast cancer (MBC) can be challenging due to the multifaceted coordination required to address their complex care. Although national guidelines exist for the treatment of MBC, they do not clearly state the best sequence of treatments, nor do they describe how and when to identify and engage patients in clinical trials. The lack of a clear process for the routine care of patients with MBC may lead to under- and over-use of care and undue patient and system burden. Using an implementation science approach to guide multilevel program adaptation, we propose adapting and evaluating the coordinated care model, Ending Metastatic Breast Cancer for Everyone (EMBRACE), from the Dana Farber Cancer Institute, to the St. Louis region. This adaptation will enhance collaboration between academic and community oncology practices to improve satisfaction and acceptability among patients and clinicians.
Theranostic approach to chemo-resistant multiple myeloma through VLA-4 imaging and nanotherapeutic targeting
Principal Investigator: Gregory Lanza, MD, PhD and Monica Shokeen, PhD Goal: To develop proof-of-concept evidence related to the therapeutic response and effectiveness of a new targeted combination nanotherapy for patients with multiple myeloma Description: Multiple Myeloma (MM) is a multifocal bone plasma cell neoplasia that causes systemic organ damage, and is characterized by a recurring and/or progressive course. Over the past two decades, new anti-myeloma therapeutics and bone marrow transplantation after high-dose chemotherapy have improved survival for many patients. However, patients with high risk mutations can rapidly progress despite treatment, and all of the responders eventually develop relapse, undergoing multiple lines of treatment. Very late antigen-4 (VLA4) is a receptor that is over expressed on MM cells and it helps MM cells to adhere to the bone stroma improving their survival and resistance to drugs. The small molecule 64Cu-LLP2A can bind with high affinity to VLA4 on MM cells, and allow their imaging by positron emission tomography (PET). 64Cu-LLP2A is able to detect MM lesions in small animal models with high precision, and is currently undergoing safety and efficacy evaluation in patients. Preliminary data suggest that VLA4-targeted therapeutic nanoparticles (20nm) may be particularly effective for treating chemoresistant MM due the increased VLA4 cell surface levels, selectively delivering anti-myeloma drugs. This project will develop proof-of-concept evidence for two fundamental hypotheses: 1) 64Cu-LLP2A signal intensity is correlated with therapeutic response to VLA-targeted combination nanotherapy, and 2) chemotherapy increases VLA4 levels on residual drug resistant MM cell membranes (R-MMC) that is recognized by 64Cu-LLP2A and predictive of the effectiveness of VLA4-targeted nanotherapy to circumvent chemoresistance. The long-term vision of this program is the use of 64Cu-LLP2A/PET to detect residual drug-resistant MM cells (R-MMC) early, triggering specifically targeted “trojan horse” nanoparticle treatments that will use this common mechanism of drug resistance to selectively treat and deplete R-MMC, to delay disease relapse, and improve patient survival.
Principal Investigator: Jeff Bednarski, MD, PhD Goal: To understand how SYK and pre-BCR signaling are negatively controlled in normal development and how these signals are disregulated in leukemic cells. Description: In pediatric pre-B acute lymphoblastic leukemia (pre-B ALL), B cell development is arrested at an early developmental stage and the leukemic blasts hijack normal developmental signaling pathways to support their survival and proliferation. Increased signaling from the pre-B cell receptor (pre-BCR) can drive the proliferation and survival of the leukemic cells. During normal B cell development, the pre-BCR signals through the SYK tyrosine kinase to coordinate both the proliferative expansion of pre-B cells and the assembly of immunoglobulin receptor genes, which proceeds through DNA double stranded breaks (DSBs). Increased SYK activity results in a block in B cell development and transformation into pre-B ALL3,5. Furthermore, pre-B leukemic blasts depend on SYK for proliferation and survival3. How SYK and pre-BCR signaling are negatively controlled in normal development and how these signals are disregulated in leukemic cells are not known. Importantly, no mutations in SYK have been identified in pre-B ALL, suggesting that changes in gene or protein expression account for the increased SYK activity in leukemia. We have identified a novel regulatory circuit that inhibits pre-BCR signaling and limits pre-B cell proliferation. The physiologic DSBs generated during immunoglobulin receptor gene rearrangement trigger DNA damage responses that suppress pre-BCR signaling. RAG DSBs mediate this cell cycle arrest by repressing SYK kinase activity downstream of the pre-BCR. The DNA damage-mediated pathway functions independent of p53, the canonical tumor suppressor. Our goal is to determine how signals from DSBs integrate with developmental programs to coordinate B cell maturation and suppress leukemogenesis. We hypothesize that signals from DSB modulates SYK activity to promote normal maturation while repressing leukemic transformation. We propose to characterize the transcriptional and post-translational mechanisms that are activated by DSBs to suppress SYK activity in early B cells. This pre-B cell specific signaling program is an attractive target for new therapies as modulation of these pathway could inhibit proliferation of leukemic cells, including those deficient in p53. These studies will provide new insight into the initiation and maintenance of leukemia.
Principal Investigator: Josh Rubin, MD, PhD Goal: To understand why males get cancer more often than females and why they don’t respond as well to therapy. Description: Males get cancer more often than females and they respond less well to therapy. These well-documented observations require a molecular explanation and a rigorous evaluation of their implications for personalized cancer treatments. We hypothesize that both phenomena are a consequence of greater adaptability in male cell populations to oncogenic and treatment-induced stress compared to female cell populations. We further hypothesize that adaptability is a consequence of greater cell population-based transcriptional heterogeneity. This we expect will be present due to the substantial sex differences in epigenetic regulation of gene expression. If correct, identifying epigenetic and transcriptional heterogeneity as the foundation for sex differences in cancer incidence and response to treatment will open new lines of investigation in cancer biology and new approaches to treatment that are designed to limit epigenetic and transcriptional flexibility. We will evaluate this hypothesis by performing RNA sequencing on male and female wildtype astrocytes and astrocytoma cells under basal growth conditions and after treatment with radiation or chemotherapy. From these data, we will construct population profiles and determine how they differ between males and females, how transformation affects them, and how treatment affects them. From this analysis, we expect to identify genes and epigenetic mechanisms that support adaptability. These findings will serve as the foundation for future mechanistic studies and future clinical trial efforts to address sex differences in cancer biology and treatment response as a path to improving outcomes for all patients. We expect that these data and this line of investigation will be fundable through a future RO1.
A feasibility study to correlate cognitive changes of IDH-mutant and IDH-wildtype glioma patients after chemoradiotherapy with radiation dose to the resting state networks
Principal Investigator: Jiayi Huang, MD, MSCI Goal: New clinical trial to better understand how an advanced imaging technology called resting-state function MRI can be used to improve radiotherapy planning to reduce its negative impact on brain function for glioma patients. Description: Gliomas are malignant brain tumors that are typically treated with chemoradiotherapy. Patients may develop problems with their mental function after chemoradiotherapy, such as worse memory and attention. We currently know our brain is organized into different networks that control various mental functions, but we do not fully understand what networks are most sensitive to radiation injury to cause the observed decline of mental function. We have this advanced imaging technology called resting-state functional MRI (RS-fMRI) that can identify different brain networks. In the proposed study, we will perform RS-fMRI and detailed cognitive tests on glioma patients before and after their chemoradiotherapy. We will correlate changes of their test scores with radiation dose delivered to different networks on the RS-fMRI. This study will provide valuable background information regarding how we can use RS-fMRI to improve radiotherapy planning in the future to reduce its negative impact on brain function.
A personalized neoantigen vaccine in patients with newly diagnosed glioblastoma using a novel DNA-based platform
Principal Investigator: Tanner Johanns, MD, PhD Goal: New clinical trial to determine the safety and immunogenicity of a novel personalized vaccine approach in newly diagnosed glioblastoma Description: Glioblastoma is the deadliest brain tumor in adults with few effective treatment options. This clinical trial aims to determine the safety and immunogenicity of a novel personalized vaccine approach in newly diagnosed glioblastoma. Neoantigens, derived from patient tumor-specific mutations, will be identified using a robust discovery pipeline, pVac-Seq, developed at Washington University. Neoantigens will be incorporated into a proprietary DNA vaccine platform in collaboration with Geneos Therapeutics that allows simultaneous expression of up to 50 neoantigens together with the potent immunostimulant adjuvant, IL-12. To date, previous neoantigen vaccine efforts have been limited to 20 candidates per patient and have failed to effectively prime CD8 T cells, which are critical for effective anti-tumor responses. If successful, the key advantages of this platform to prime robust CD8 T cells responses to a larger number of neoantigen candidates will serve as a new standard for neoantigen vaccinations in glioblastoma and other tumor types.
Principal Investigator: Brian Dieckgraefe, MD, PhD Goal: To develop ways to block a newly discovered pancreatic cancer signaling pathway that drives cancer growth and resistance to therapy. Description: Pancreatic cancer has the worst patient survival among all digestive tract cancers. Recent discoveries recognized that a population of human cells, termed as cancer stem cells are critical for tumor growth, its spread to other organs, therapy resistance, post-treatment recurrence and patient survival. We recently discovered a novel signaling pathway that is active in pancreatic cancer, as well as other cancers, that increases tumor growth and treatment resistance. A signaling molecule, called Regenerating gene 4 protein (Reg4), binds to the cell surface CD44 receptor, and directs clipping and release of a small protein peptide (the intracytoplasmic domain, CD44ICD) first into the cytoplasm and then into the nucleus of the cell. Inside the nucleus, CD44ICD turns on other pathways (gene programs) that appear to be responsible for rapid cancer growth. Like a conductor in an orchestra, this single peptide directs multiple different ‘instruments’ or pathways that are used by tumors to grow rapidly and resist treatment. In this proposal, we are attempting to fully understand how CD44ICD works by identifying how it interacts with other critical cellular/nuclear proteins in pancreatic cancer. Results of this study will be used to design new drugs for pancreatic cancer treatment.
Principal Investigator: Eric Kim, MD Goal: To test the accuracy of a newly developed imaging tool in correctly predicting prostate cancer grade in patients non-invasively. Description: Prostate cancer is the most common cancer among men in the United States. Unfortunately, the standard approach to diagnose prostate cancer requires a transrectal prostate biopsy, which is a very uncomfortable, invasive procedure that has medical risks such as sepsis. Prostate magnetic resonance imaging (MRI) has helped reduce unnecessary biopsies, but remains insufficiently accurate (e.g. false positive rate >35%, false negative rate >15%). Our research team has developed a new tool for MRI analysis–diffusion basis spectrum imaging (DBSI). Using DBSI, we can non-invasively distinguish prostate cancer from cancer-imitators. We can also use DBSI to accurately predict the prostate cancer grade in tumor samples. We plan to use DBSI on men who are undergoing prostate biopsy as per clinical care, to show that DBSI can non-invasively predict the biopsy results. If we are successful, we hope that DBSI can replace the majority of transrectal prostate biopsies.
Principal Investigator: Quing Zhu, PhD Goal: To accurately assess and predict rectal cancer patients’ response to neoadjuvant radiation and chemotherapy and to select the best surgical strategy for each individual patient. Description: Rectal cancer is a prevalent disease that requires complex and coordinated care to achieve maximal survival while preserving a patient’s quality of life. Globally, 704,376 new cases of rectal cancer were reported in 2018, and over 310,000 people died of this disease. Advances in the pre-operative treatment of these cancers have enabled 20-35% of locally advanced rectal cancer patients to achieve complete tumor death with radiation and chemotherapy alone. In these individuals, surgical resection has shown no benefit and poses a significant risk of major complications, prolonged recovery, and reduced quality of life. However, the standard of care testing cannot adequately differentiate residual cancer from completely eradicated tumor sites in the treated rectum. In most instances, due to the uncertainty of post-treatment evaluation, physicians err on the side of over-treatment and operate on all eligible candidates. To assess rectal cancer patient treatment response before surgery, we have developed a new endoscopy imaging system using photoacoustic microscopy and ultrasound. We will optimize our prototype system, develop a novel machine learning approach to accurately identify residual cancer from the treated tumor bed with scar tissue and conduct a pilot patient study.
Principal Investigator: Gregory Longmore, MD and Amit Pathak, PhD Goal: To determine the contribution of multiple environmental signals within breast tumors to metastasis. Description: The majority of breast cancer deaths result from metastatic disease. Accumulated evidence indicates that breast tumor cells invade as complex, heterogeneous clusters rather than single cells and to do so they are led by cells called leader cells. Several hypotheses have been proposed to explain cancer leader cell development during collective migration. Yet how these leader cells develop, arrive and define the front edge, then lead directed collective migration, and whether this phenomenon is necessary and sufficient to effect directed collective migration are largely unknown. We have developed novel microfluidic devices in which to study the collective migration. In the present proposal, we propose to determine how leader cells develop and function, in response to multiple environmental signals, so as to direct collective migration.
Principal Investigator: Stephanie Perkins, MD; Adam Bauer, PhD; Timothy Mitchell, PhD; and, Francisco Reynoso, PhD Goal: To study the effects of radiation therapy on brain function and cognition to gain a comprehensive understanding of radiation-induced brain injury. Description: Radiation therapy is integral for achieving tumor control in many adult and pediatric brain tumors, but it can often lead to debilitating side-effects on patients’ brain function and cognition. As survival outcomes improve, there is an increased need to improve quality of life for brain tumor survivors. The primary goal of the application is to study the effects of radiation therapy on the mouse brain to gain a comprehensive understanding of radiation-induced brain injury. Towards this goal, we will examine how whole brain radiation alters brain network communication and behavioral performance, and how these changes relate to cellular and molecular markers of brain injury. The ultimate goal of this project is to develop and test therapeutic interventions in mice that could prevent or reverse radiation-induced injury in humans.
Principal Investigator: Milan Chheda, MD Goal: To develop treatments that will become the new standard of care for patients with glioblastoma. Description: Glioblastoma (GBM) kills most adults within 2 years. Despite surgery, radiation, and temozolomide (TMZ) chemotherapy, most GBMs recur within 6 months. There is no standard of care for recurrent GBM. Recurrence and treatment resistance is driven, in part, by the existence of cancer stem cells, poor anti-tumor immunological response, non-optimal dosing of chemotherapy, and inadequate penetration of drugs across the BBB and throughout the tumor. The Washington University GBM Team Science Group is composed of highly collaborative and interactive physician scientists with complementary expertise in immunotherapy, cell signaling, blood-brain barrier (BBB) biology, and clinical trial design. Our pre-SPORE proposal will address each of these barriers to progress. Project 1 will perform pre-clinical testing, with toxicity studies, of Zika virus as a new therapy for GBM. Project 2 will characterize newly discovered cells in the brain that may modulate an anti-tumor defense, and optimizes therapies to enhance their function in patients. Project 3 develops our next clinical trial using laser ablation, pioneered at Washington University, in combination with the best therapy to kill GBM cells and initiate a powerful anti-tumor immune response. Project 4 builds on the fact that we are the only institution in the country performing circadian rhythm-based cancer treatment, and prepares us to launch a clinical trial based on optimal timing and combination therapy to substantially improve patient outcomes.
Principal Investigator: Jeff Magee, MD, PhD Goal: To develop new strategies to model and treat pediatric acute myeloid leukemia (AML). AML therapies are extremely toxic, and they have not evolved much in the past several decades. This lack of progress underscores a need for newer, rationally designed pediatric AML therapies. Description: Pediatric leukemias act different than adult variations, even if the leukemias look the same under the microscope. The mutations are different and we are trying to understand why. We think that changes that take place during normal blood development can help account for the differences. If we can give cells an “identity crisis” and make them “think” that they are a different age or identity than they really are, we might be able to negate the effects of certain mutations. Childhood AMLs can have many different mutations in many different combinations. The combinations may determine whether a given therapy is effective or not. It is difficult to understand this level of complexity by simply studying patient samples, yet it is also difficult to model complexity in the laboratory. We are developing new tools using modern technology that will allow us to understand how certain combinations of mutations change biology and drug responses.
Principal Investigator: Joshua B. Rubin, MD, PhD Goal: To gain a better understanding of why children have not survived their brain tumor diagnosis and to help neurosurgeons have a better understanding of where to biopsy their patients. Description: The Legacy Program is a unique collaboration — between a team of neuro-oncologists at Washington University School of Medicine and their patients — to use post-mortem brains with tumors still in their original condition to investigate why these tumors are therapy resistant. Taking a three-tiered approach, the first step is to use experimental imaging to better define the extent of disease at the time of death. Preliminary results suggest that clinically available anatomical MRI, the standard in brain tumor imaging, underestimates the extent of brain tumor dissemination, which may be a significant contributor to treatment failure. Because surgery and radiation therapy are the basis of successful brain tumor treatment, underestimation of the extent of disease may be a significant contributor to treatment failure. Second, using next generation sequencing of multiple post-mortem imaging directed “biopsies,” the team is reconstructing the mutation of cells in the recurrent tumors. The team has discovered that large scale chromosomal copy number gains and losses are present at the time of diagnosis in children who do not survive their brain tumors. If these finding are validated through this project, it could provide an early method for identifying those children who are not likely to be cured by standard treatments and would allow doctors to consider alternative approaches in the early stages of treatment. Finally, we are using histology (microanatomy of cells, tissues and organs), sequencing and imaging results to create a reference guide of tumor diversity as it relates to the surrounding brain. We expect that regional differences in brain structures, hypoxia (absence of enough oxygen in the tissues to sustain bodily functions) and immune infiltration, among other differences, might allow multi-component mapping to optimally deliver radiation therapy and other spatially focused interventions such as ultrasound. Together, we believe that these studies can be translated as new treatment designs that anticipate resistance mechanisms and prevent recurrence of brain tumors. Since establishing this program as a collaboration between physicians, scientists and families, the emotional impact of the program and its name has become evident. The team stays in contact with donor families and have hosted one retreat to which all families were invited to listen to research updates and to engage in open discussion with the investigative team. Families report that The Legacy Program provides ongoing hope that some good can still come from the suffering of their child, parent or sibling.
Investing in quality equipment is critical in enabling the expansion of current laboratory activity. State-of-the-art equipment purchases such as this one help recruit and retain top scientists and staff as we continue to grow. Children’s is in constant competition for the nation’s most distinguished physicians, researchers and teachers. There is a diminishing workforce of pediatric physician-scientists and a worrisome decline in federally funded pediatric research. Fewer pediatric researchers must do more with less, but this purchase ensures our laboratories here at Children’s in conjunction with Washington University School of Medicine will have access to the best technologies available. With funds raised by Pedal the Cause, the FACSAria Fusion cell sorter has been identified and purchased as an equipment upgrade vital to pediatric cancer research. A fully integrated advanced cell sorter and biosafety solution for research laboratories, the machine features high-performance cell analysis and is capable of high speed and single cell sorting on up to sixteen parameters.
Phase I trial of best-in-class JAK inhibitor, baricitinib, as prophylaxis of Graft versus Host disease (GVHD) in patients undergoing allo-HCT for hematologic malignancies
Principal Investigator: Mark Schroeder, MD Goal: To explore whether blood cancer patients who receive blood or marrow transplants experience less Graft versus Host Disease when given baricitinib. Description: Blood cancers remain a significant public health problem (~10% of new cancer diagnoses). These patients can often be cured by blood or marrow transplants. However, in about 50% of cases the donated immune system sometimes attacks the patient’s skin, intestines, and liver. This very debilitating and sometimes fatal condition (~25% of victims) is known as Graft versus Host Disease (GvHD). In our first-in-human phase I clinical trial we will explore whether blood cancer patients who receive blood or marrow transplants experience less GvHD when given baricitinib. In studies in mice, baricitinib was shown to prevent GVHD while allowing the immune cells to retain their ability to attack the cancer cells. Our hope is that this simple approach will improve transplant outcomes by decreasing a major side effect after transplant, result in cures of blood, bone marrow, and lymph node cancers, and provide a significant step forward in the field.
Principal Investigator: Zhongsheng You, PhD and Matthew Walter, MD Goal: To test if targeting a particular RNA degradation pathway in cells with spliceosome gene mutations (responsible for multiple types of cancer) is a viable strategy to treat cancer. Description: RNA splicing is an important process in cells that cuts and stitches RNA segments together to generate mature RNA required for normal cell function. Many blood cancers and solid tumors are caused by mutations in genes that regulate RNA splicing (i.e., spliceosome genes). Cells with these mutations produce many abnormal RNAs, including nonsense messenger RNAs which can generate abnormal proteins that cause deleterious effects, including cell death. Because nonsense messenger RNAs are normally cleared up by the nonsense-mediated mRNA decay (NMD) pathway in cells, we hypothesize that inhibiting the NMD pathway can kill cancer cells with spliceosome gene mutations. Building on our preliminary results and the complementary expertise and strengths of two labs, we propose in this project a series of innovative studies to test the idea that targeting NMD is a viable therapeutic strategy for cancer treatment.
Principal Investigator: Li-Shiun Chen, MD, MPH, ScD and Aimee James, PhD, MPH Goal: To reduce the high smoking prevalence in rural communities with a multi-level strategy to help patients quit smoking and reduce health disparity in rural communities. Description: Smoking is a leading modifiable risk factor for disability and death in patients within rural communities. Rural southern Illinois, part of the Siteman Cancer Center catchment area, has high prevalence of smoking and lung cancer. There is a tremendous need for offering of smoking cessation treatment in these rural clinics. By overcoming barriers in rural clinics such as long travel distances to access care, lack of training, and infrequent service utilization, this study will test the effect of a low-burden, multi-level strategy in rural health clinics to help these patients quit smoking. This innovative research will leverage technology to assess smoking and facilitate consistent delivery of evidence-based cessation treatment at low burden and low cost to the rural health clinics. Our study will set the foundation for a future successful implementation trial (R01 grant) of a multi-level strategy to reduce smoking in rural communities. This project is significant because these implementation strategies can be easily disseminated and have the potential to significantly reduce smoking and associated disability and death in patients within rural communities.
Principal Investigator: Christopher Maher, PhD Goal: To better understand how a fusion gene causes tumor growth in 11 different cancer types and ultimately identify a targeted therapy to inhibit the fusion genes and ultimately prevent cancer progression. Description: Our lab has extensive experience identifying regions of the human genome that are “rearranged” as a tumor develops. This process results in two completely independent genes becoming “fused” together (referred to as a ‘fusion gene’). Since fusion genes are specific to tumor cells they represent ideal diagnostic and prognostic markers. Novel therapies targeting the fusion gene are also more effective by killing cancer cells without affecting normal cells. Therefore, this study focuses on our recently discovered novel fusion gene that was observed in patients with 11 different cancer types. This study will focus on understanding how the fusion gene promotes tumor progression. This research is critical to achieve our longer-term goal to “drug” this fusion gene using existing FDA approved drugs. This will be of broad impact given the large patient population that has the fusion gene.
Development of Novel ERK Inhibitor-Based Therapeutic Combinations In Pancreatic Cancer Based On Proteo-Transcriptomic Analyses
Principal Investigator: Kian Lim, MD, PhD Goal: To develop new therapeutic strategies that can more effectively target the activated signaling pathway in pancreatic cancer and ultimately improve patient outcomes. Description: Effective treatment for patients with pancreatic cancer is an urgent, unmet medical need. Targeting the cancer-driving events within pancreatic cancer cells bears the highest chance of therapeutic breakthrough. Pancreatic cancer is characterized by activation of a signaling pathway called the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is analogous to a “gas pedal” in a car, and in normal cells is tightly controlled by many “braking” mechanisms. In pancreas cancer, this gas pedal is constantly engaged due to a near universal mutation of the KRAS gene. For decades, attempts to slow down the MAPK pathway has not been successful, and all evidence point towards ERK, a critical signaling node within the MAPK pathway, that is very difficult to suppress. Using patient samples and cell lines studies we have now uncovered a novel mechanism by which cancer cells can resist ERK inhibition. Our proposal focuses on developing novel combinatorial therapeutic strategies that can more effectively curb ERK to improve patient outcome.
Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome
Principal Investigator: Andrea Hagemann, MD Goal: To create a standard toolkit for cancer providers to utilize for cancer patients with inherited disease-causing genetic mutations and their family members in educating on the importance of undergoing genetic testing. Description: Currently, cancer patients with inherited disease-causing mutations such as BRCA1 or BRCA2 bear the burden of educating their family members about the need to undergo genetic testing. There are currently no standard methods for cancer providers to help their patients with this. Once family members are tested, they may not have easy access to prevention strategies. This project tests a toolkit to be used by providers, patients with mutations (probands) and family members, containing educational materials, testing options, and counseling and treatment resources. If this toolkit is successful, then further studies and large-scale implementation could allow thousands of people each year to learn of their cancer risk and undergo early screening or treatments, preventing many cancers altogether.
Principal Investigator: Obi Griffith, PhD and Jeffrey Bryan, DVM, MS, PhD, DACVIM Goal: To develop new methods for measuring immune therapy response and resistance in companion dogs and ultimately create a powerful new system for understanding and improving immune therapies in both humans and companion animals. Description: Immune therapies show promise in treating deadly cancers, but failures are not predictable and responses can be brief. Companion dogs develop many of the same cancers as people do for many of the same reasons and in a similar immune environment. This is an ideal setting to understand why immune therapies succeed or fail in cancer patients. However, many of the necessary tools and computational approaches used to study the immune system in humans and mice are under-developed for dogs. We will develop new methods for measuring immune therapy response and resistance specifically for use in dogs. This will help create a powerful new system for understanding and improving immune therapies in both humans and companion animals. In this study, by testing canine (dog) melanoma with widely used immune therapies from human medicine, we hope to better understand why some patients respond, some patients fail, and why resistance develops.
Principal Investigator: Stefanie Geisler, MD Goal: To investigate different therapeutic strategies that block a mechanism that leads to nerve fiber damage during chemotherapy treatment and ultimately prevent chemotherapy-induced neuropathy. Description: Many commonly used chemotherapy regimens have as side effect peripheral neuropathy. Chemotherapy-induced neuropathy is characterized by numbness, tingling, burning pain, imbalance and weakness in hands and feet. In contrast to other side effects, the neuropathy can last long after chemotherapy has ended and cause permanent disability. There are no treatments that can prevent chemotherapy-induced neuropathy. Others and we have identified mechanisms that lead to nerve fiber damage during chemotherapy. We discovered that different chemotherapeutics activate a protein called SARM1, which rapidly breaks down the essential metabolite (fuel) NAD+, thereby leading to metabolic collapse and nerve fiber breakdown. Here, we will investigate different therapeutic strategies that block this final common axon destruction pathway in an animal model. These are important steps toward translating our findings to the clinic, where such a therapy could benefit millions of cancer patients.
Principal Investigator: Roberta Faccio, PhD Goal: To investigate the effects of neutralizing a factor produced by bone cells, in conjunction with chemotherapy and/or immune therapy, to increase the efficacy of these cancer therapies in breast cancer. Description: Although the majority of breast cancer cases are diagnosed early, approximately 10-20% of patients recur within 10 years. Unfortunately, once the tumor cells spread to various organs treatment options are limited. Immune therapy, aimed at increasing the tumor killing power of the patient’s immune cells, has transformed cancer treatments in recent years giving hope to patients previously considered terminal. However, the response rate to immune therapy on breast cancer is low. We recently discovered that a factor produced by the bone cells, Dkk1, is increased during tumor progression and creates an “immune suppressive environment” where the very cells that could destroy the tumor (T cells and NK cells) are unresponsive, allowing tumor cells to grow undisturbed. Dkk1 correlates with poor outcome in breast cancer. Thus, we will investigate the effects of Dkk1 neutralization, in conjunction with chemotherapy and/or immune therapy, to bolster anti-tumor immune responses and kill resistant tumor cells.
Functional characterization of an uncharacterized cytokine, Gm525, as a potential target for cancer therapies
Principal Investigator: Takeshi Egawa, MD, PhD Goal: To better understand and test a recently discovered phenomenon in which cancer cells promote their own growth by releasing a molecule and develop tools to inhibit this cancer promoting mechanism. Description: We do not completely understand how cancer arises from normal cells. While errors in copying the genome during cells division and subsequent changes in gene expression are major drivers for cancer development, it is predicted that there are additional causes that increase the risk of cancers or make cancer resistant to therapies. In our recent studies using mouse models of leukemia, which is a cancer derived from blood cells, we have found an intriguing phenomenon, in which cancer cells produce a soluble factor, like a hormone, which may promote their own growth. In this project, we will perform additional studies to test whether this is a common cancer promoting mechanism shared by various cell types and also develop tools to suppress cancers by inhibiting this mechanism. We expect this study will lead to the development of a new therapy that is distinct from conventional methods.
Principal Investigator: Kyunghee Choi, PhD Goal: To develop a drug to block abnormal tumor blood-vessel formation in order to enhance cancer immunotherapy treatment. Description: Tumor blood vessels are known to be abnormal, dilated, leaky, tortuous, and have slow blood flow. Recent studies have suggested that normalizing such abnormal blood vessels might enhance cancer immunotherapy. As such, there is a great interest in the combined cancer blood-vessel therapy and immunotherapy. However, current major blood-vessel drugs, mainly targeting the vascular endothelial growth factor (VEGF) or VEGF receptor 2 (VEGFR2), have proven to be suboptimal, largely due to limited effectiveness, serious side effects and high cost. As such, discovering new targets may improve the current limitations of cancer blood-vessel therapy. We identified MycT1 to be such a molecule. MycT1 was specifically required for tumor blood-vessel formation. Combined treatment using a strategy to knock-down Myct1 expression with immunotherapy was highly effective in inhibiting tumor growth. Based on these exciting preliminary data, we will develop a drug against MYCT1 to block its function, and assess its efficacy in cancer treatment together with immunotherapy.
Principal Investigator: Russell Pachynski, MD Goal: To analyze immune responses from metastatic prostate cancer patients currently in a clinical trial designed to test a combination of immunotherapies, including a personalized vaccine. Description: Despite the success of immunotherapy in many tumors, response rates in prostate cancer have been disappointingly low. The current front-line treatment for metastatic prostate cancer slows down the disease and usually puts patients into a temporary “remission” of sorts, but does not cure it, and lethal, resistant prostate cancer then recurs. Our study uses a combination of immunotherapies given to patients after initiation of standard front-line therapy in order to stimulate the immune system to eradicate the residual prostate cancer. We are utilizing a PSA-based viral vaccine in combination with two other immune-stimulating drugs. We then use a personalized vaccine made from each patient’s tumor tissue- termed a “neoantigen” vaccine, also in combination. Over the treatment course, we will collect samples to analyze immune responses to this combination immunotherapy strategy, and correlate these with patient outcomes. This is the first trial of this combination of immunotherapies and personalized vaccines in metastatic prostate cancer patients.
Principal Investigator: Jian Campian, MD, PhD Goal: To better understand the mechanisms of a new drug currently in clinical trials that is designed to restore the immune status in patients with gliomas receiving radiation and chemotherapy. Description: Impaired immune system is common in cancers such as malignant brain tumors. The current standard of radiation and chemotherapy can decrease the numbers of immune cells (lymphocytes). Decreased lymphocytes is associated with shorter survival for patients with a variety of cancers. This study is the first to test if a novel interleukin-7 analogue, rhIL7hyFc, can increase lymphocytes and restore immune status in patients treated with standard radiation and chemotherapy for their brain tumors. The clinical trial is ongoing. Preliminary data suggest rhIL-7hyFc can increase lymphocytes. The current proposal is to perform novel correlative studies to better understand the mechanism and the full impact of rhIL-7hyFc treatment on immune modulation in brain tumors. The findings from this study will have an impact on the use of rhIL-7hyFc in combination with other immunotherapy treatments such as checkpoint inhibitors, vaccines, or oncolytic virus in the treatment of malignant brain tumors.
A Single-Arm Phase II Study with a Safety lead-in of Magnetic Resonance-Guided Hypofractionated Adaptive Radiation Therapy with Concurrent Chemotherapy and Consolidation Durvalumab for Inoperable Stage IIB and IIIA Non-small Cell Lung Cancer
Principal Investigator: Gregory Vlacich, MD, PhD Goal: To study through a clinical trial whether higher doses of radiation delivered safely with chemotherapy using a unique, cutting edge MRI-guided radiation delivery system followed by standard-of-care immunotherapy will improve tumor control and survival in non-small cell lung cancer. Description: In the United States, non-small cell lung cancer is the leading cause of cancer-related death. For individuals with non-metastatic, but advanced disease, a large percentage who receive the current standard therapy continue to fail treatment at or near the original sites of disease, and this is directly correlated with worse survival. New approaches to reduce these failures are necessary to improve the chance for cure. In our clinical trial, we explore the use of a unique, cutting edge MRI-guided radiation delivery system to improve tumor control by delivering significantly higher doses of radiation per treatment than conventional radiation. Through improved image resolution with MRI and real-time treatment adaptation, higher dose can be achieved with this system through enhanced protection of organs surrounding the tumor. We propose that higher doses of radiation delivered safely with chemotherapy using our MRI-guided system followed by standard-of-care immunotherapy will improve tumor control and survival.
Principal Investigator: Nima Mosammaparast, MD, PhD Goal: To study the reasons behind the sensitivity of cardiac cells to common chemotherapeutics to be able to come up with effective means to counter heart failure in cancer survivors. Description: While many commonly used chemotherapies used in cancer can be effective for the tumor itself, they cause long-term side effects in survivors. It is well-established that cancer survivors often develop heart disease or heart failure as a result of the chemotherapeutics they are given. However, the molecular and cellular mechanisms that cause this in the heart are not known. We propose that certain cells that reside in the heart, called cardiac macrophages, are particularly sensitive to commonly chemotherapeutics used for cancer treatment. We propose to study the reasons behind this sensitivity to be able to come up with effective means to counter heart failure in cancer survivors.
Principal Investigator: Jinsong Zhang, PhD Goal: To study a recently discovered mechanism in cancer cells that can switch on and off genes that suppress tumors and genes that promote tumors and ultimately explore its use as a new cancer target and new class of cancer drugs. Description: Cancers result from altered levels of tumor suppressor genes (genes that suppress tumors) and oncogenes (genes that promote tumors). Histone deacetylase 3 (HDAC3) can reduce gene levels, and its inhibitors are used to treat cancers by increasing tumor suppressor levels. However, these inhibitors are not specific to HDAC3 and therefore can result in unwanted side effects, preventing their use in most cancers. They also have a limited ability to treat cancers induced by oncogenes. We have recently discovered a new HDAC3-specific mechanism that can switch HDAC3 on and off for different genes, including tumor suppressors and oncogenes. This proposal will further study this mechanism in cancer cells, determine the molecular basis, and explore its use as a new cancer target, both to increase tumor suppressors and decrease oncogenes. The ultimate goal is to develop a new class of cancer drugs with improved specificity and enhanced abilities to treat various cancers in the coming era of personalized medicine.
Principal Investigator: Jeffrey Magee, MD, PhD Goal: To better understand the biology of pediatric leukemia cells that are left after cancer therapy and try to identify the genes that enable these leukemia cells to resist such cancer treatment. Description: Acute myeloid leukemia (AML) accounts for approximately 25% of childhood leukemias. AML is often difficult to treat, and even successful treatments can leave children with lifelong disabilities. Childhood AML is often caused by different mutations than adult AML. This is not a hard and fast rule – some mutations are found in both ages – but certain mutations skew heavily toward the pediatric population. This raises the question of whether drugs that target mutant proteins might have different effects on childhood and adult AML. We propose to test this possibility. We are particularly interested in understanding the biology of leukemia cells that persist after therapy. Our preliminary data suggest that AML cells may have fundamentally different patterns of DNA organization when they persist in children as compared to adults. We will identify genes that sustain drug resistant childhood AML cells with the goal of developing new treatment strategies.
Principal Investigator: Charles Kaufman, MD, PhD Goal: To better understand how a key gene in melanoma is controlled and its role in the earliest mechanisms regulating the formation of melanoma and ultimately identify new potential treatment targets. Description: While many cancer patients initially respond to targeted anticancer therapy, these drugs eventually stop working, which is one of the biggest challenges in the treatment of lung cancer patients. Hepatocyte growth factor (HGF) allows the growth of tumor in the presence of anticancer therapy. Levels of HGF are increased in the blood and tissues of lung cancer patients that do not respond to targeted therapy with shrinking of the tumors. Currently, there is no approved drug that would block the activity of HGF. We have discovered unique inhibitors of the three serine proteases, HGF-Activator, matriptase and hepsin, which prevent the activation of HGF. We have shown that our lead compound VD2173 significantly improves the response of human cancer cell lines to clinically used therapeutic agents. The goal of this project is to demonstrate that VD2173 both overcomes and prevents resistance to targeted therapy in mouse models of lung cancer; a necessary step in the preclinical development of VD2173 as a new drug for lung cancer patients.
Principal Investigator: James Janetka, PhD Goal: To test whether small molecule protease inhibitors developed in my lab are effective at overcoming and preventing resistance to anticancer therapy in lung cancer animal models. Description: While many cancer patients initially respond to targeted anticancer therapy, these drugs eventually stop working, which is one of the biggest challenges in the treatment of lung cancer patients. Hepatocyte growth factor (HGF) allows the growth of tumor in the presence of anticancer therapy. Levels of HGF are increased in the blood and tissues of lung cancer patients that do not respond to targeted therapy with shrinking of the tumors. Currently, there is no approved drug that would block the activity of HGF. We have discovered unique inhibitors of the three serine proteases, HGF-Activator, matriptase and hepsin, which prevent the activation of HGF. We have shown that our lead compound VD2173 significantly improves the response of human cancer cell lines to clinically used therapeutic agents. The goal of this project is to demonstrate that VD2173 both overcomes and prevents resistance to targeted therapy in mouse models of lung cancer; a necessary step in the preclinical development of VD2173 as a new drug for lung cancer patients.
Principal Investigator: Michael Holtzman, MD Goal: To further study a new cause of triple-negative breast cancer and a new drug candidate in cell and animals models and ultimately transition this drug into human clinical trials. Description:This proposal addresses the challenge of understanding and treating breast cancer, which is projected for 41,000 deaths for 2018 despite any of the current therapeutic approaches. The project is specifically focused on the 15-20% of breast cancer that cause these deaths, generally because they are negative for hormone and growth factor receptors and are therefore not specifically targeted by any current treatments. Here we will pursue our discoveries of a new cause of severe forms of breast cancer and a new drug candidate that corrects this mechanism in cell and animal models. We will use these models to validate our proposed pathway to breast cancer and will optimize the effectiveness and safety of our new drug for blocking breast cancer. These results will form the basis of a new paradigm for breast cancer and the next and final phase of studies needed for clinical trials in humans with breast cancer.
Principal Investigator: Colin Flaveny, PhD Goal: To determine the efficacy of a newly developed drug designed to make metastatic prostate cancer vulnerable to existing cancer immunotherapy treatments which are notoriously ineffective. Description: Prostate cancer is the most diagnosed and leading cause of cancer related death in men, except for skin cancer. The vast majority of prostate cancer patients succumb to recurrent metastatic disease, which is normally resistant to treatment. Therefore, there is an urgent need to develop new therapies that disrupt metastatic prostate cancer growth in order to save lives. One approach to developing effective treatments is to target the biological processes that allow prostate cancer cells to grow unchecked. Prostate cancer cells are uniquely dependent on fat or lipid production, which is used to fuel growth, facilitate chemotherapy drug-resistance and allows cancer cells to evade detection and destruction by the immune system. Clinically used treatments that harness the tumor-killing properties of the immune system, such as immune-checkpoint blockade inhibitors, have been very successfully used to treat lung and skin cancer. Unfortunately, these drugs are ineffective at treating prostate cancer. We have discovered that lipids released from tumor cells suppress the activity of tumor-killing immune cells by activating the Liver-X-Receptor (LXR), a key regulator of immune function. Therefore, we hypothesized that LXR can be targeted to induce immune-destruction of prostate tumors. We have successfully developed an LXR-targeting drug that stimulates immune cells to destroy prostate tumors by preventing tumor lipids from inhibiting immune function. This project is designed to comprehensively determine if LXR drugs are effective treatments by profiling their activity in clinically relevant mouse models that recreate all aspects of prostate cancer progression in humans. We will also determine if our LXR drugs can be used to sensitize prostate tumors to clinically used immune-checkpoint blockade inhibitors. Our investigations should lead to the development of an exciting novel class of prostate cancer drugs that potently disrupts tumor growth and reduces prostate cancer mortality.
Principal Investigator: Laura Schuettpelz, MD, PhD Goal: To investigate the tetraspanin family member CD53 as a therapeutic target in B-lineage hematopoietic malignancies. Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and the majority of ALL cases originate from precursors of the B-cell lineage (B-cell precursor ALL, or BCP-ALL). While outcomes for pediatric patients with standard-risk BCP- ALL are good, the prognosis for those with relapsed disease or tumors with high-risk features remains poor. Thus, new therapies are needed. Description: Preliminary data from our lab and others demonstrates that CD53 expression is induced during early B cell development, and may play a role in protecting both normal and malignant B cells from apoptosis. CD53 is a member of the tetraspanin family of transmembrane proteins that interact with various binding partners on the cell surface and regulate a wide array of cellular processes such as proliferation, migration and survival. CD53 expression is largely confined to the hematopoietic system, where it is found on a variety of hematopoietic cell types.
Principal Investigator: Jeff Magee, MD, PhD Goal: To develop engineered stem cells that are engineered to express any fusion protein, at any time in development, and in any cell type that the researcher chooses. Description: Unlike adult cancers, a large percentage of pediatric cancers have a type mutation called a translocation. A translocation occurs when two different chromosomes break apart (usually within a gene) and then fuse together to form two entirely new chromosomes. We now know that different types of tumors absolutely require these fusion proteins to survive. If we can degrade or disrupt these linchpins, the cancers die. In other words, these fusion proteins are the cancers’ “Achilles heels.” While the importance of different types of fusion proteins is widely recognized, efforts to target these proteins with drugs has lagged for technical reasons. We lack good tools for studying fusion proteins such as cells lines, mouse models and patient samples. These tools permit us to recapitulate all steps of cancer development.
Principal Investigator: Jeff Bednarksi, MD, PhD Goal: The goal of this proposal is to define the determinants of the cellular response to DNA injury in early B cells that promote normal maturation and prevent leukemic transformation. Description: B-cell acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Yet, despite concerted efforts, we still lack an understanding of the basic mechanisms underlying its pathogenesis. Mutations and chromosomal translocations in oncogenes are key transformative events in pediatric ALL. These genetic alterations are caused by errors in the generation or response to programmed DNA breaks that occur during normal B cell maturation.
Principal Investigator: Mark Warchol, PhD and Lavinia Sheets, PhD Goal: Cisplatin chemotherapy is widely used in the treatment of pediatric cancers, but it also causes both hearing loss (ototoxicity) and nerve damage (neuropathy) in a high percentage of treated patients. The cellular mechanisms underlying these pathologies are poorly understood. Description: Our studies will use novel zebrafish models of ototoxicity and sensory neuropathy to address the following three aims: 1) Determine whether the circadian clock within sensory cells influences their susceptibility to cisplatin. 2) Establish whether pre- or co-treatment with the corticosteroid dexamethasone can reduce sensory pathology caused by cisplatin. 3) Perform a high-throughput screen of FDA approved drugs and bioactive compounds aimed at identifying small molecules that can either prevent or reverse neuronal damage caused by cisplatin. The results could lead to improved approaches to reduce and/or treat ototoxicity and nerve damage in children undergoing chemotherapy with cisplatin.
Principal Investigator: Dustin Baldridge, MD, PhD; Barak Cohen, PhD; Christina Gurnett, MD, PhD; Malachi Griffith, MD, PhD; Obi L. Griffith, PhD; Joshua B. Rubin, MD, PhD Goal: Advances in sequencing technology are fueling the rapid discovery of genetic variants in cancer, but the ability to interpret whether or not these variants actually affect the function of the encoded protein is often challenging. Instead, “look-up” tables are needed to provide physicians information about the functional impact of any possible genetic variant. We have pioneered several high-throughput functional methods and propose to refine and implement these tools to generate these tables for two important pediatric cancer genes, TP53 and SMAD4. Description:Proposed specific aims: Leverage advances in DNA mutagenesis and DNA sequencing to perform Deep Mutational Scans to study the effects of all possible gene variants affecting the protein sequences of TP53 and SMAD4. Perform additional detailed assays on all possible protein sequence mutants in TP53, and use machine learning algorithms to develop classifiers to more accurately predict variant pathogenicity. The results of these high-throughput functional studies will be immediately useful for patient care, and could also identify patient-specific novel therapeutics.
Principal Investigator: Todd Fehniger, MD, PhD and Brad Kahl, MD Goal: To develop and evaluate new treatments for patients with incurable lymphomas. Description: The goal of this Team Science program is to develop and evaluate new treatments for patients with incurable lymphomas. Our team has complementary expertise in immunology, immunotherapy, genomics, epigenetics, cancer biology, and clinical trial design are leveraged to advance new types of lymphoma therapies. The long-term goals of this team science proposal are to advance novel basic findings in lymphoma into the clinic via development of a comprehensive and innovate translational research program. Specific projects seek to:
- Investigate new immunotherapy treatment combinations in early phase clinical trials to boost indolent lymphoma patients’ natural killer (NK) cells, and to further enhance NK cell targeting of lymphoma cells via modification with specialized chimeric antigen receptors (CAR);
- Understand how changes in lymphoma cells’ DNA (mutations) result in follicular lymphoma, and translate these genetic findings into new ways to help with lymphoma patient prognosis and develop new personalized lymphoma-specific vaccine therapies;
- Develop a next-generation ‘universal’ CAR T cells to reduce barriers to lymphoma patients receiving CAR- modified T cellular therapy, and explore new strategies to enhance CAR T cell persistence;
- Determine how changes in the structure of DNA (epigenetic) impact response to treatment and progression in very hard to treat T cell lymphomas; and
- Understand the role of key activated receptor pathways (growth signals) for aggressive T cell lymphoma/leukemia, and advance a new combination clinical trial of chemotherapy combined with a growth pathway inhibitor.
Genomic Classification and Targeted Immunotherapy of Disseminated Tumor Cells (DTCs) in Breast Cancer Patients
Principal Investigator: Rebecca Aft, MD, PhD; Mark Watson, MD, PhD; and Leonel Hernandez-Aya, MD Goal: To better understand how to develop new therapies to eliminate disseminated tumor cells in triple negative breast cancer patients in order to prevent the breast cancer from metastasizing. Description: Treatment of triple negative breast cancer (TNBC) is challenging since there are a limited number of new and highly effective therapies. This subset of breast cancer patients have a high risk of disease recurrence and death when traditional chemotherapy is used. Small deposits of disseminated tumor cells (DTCs) released from the breast tumor, detected in the bone marrow (BM) of some TNBC patients before and after chemotherapy treatment, identifies patients with a particularly high risk of developing metastatic disease. It is thought that metastatic disease develops in these patients because these tumor cells themselves are resistant to therapy and because other environmental factors selectively support their growth and survival. We have developed a very sensitive 8-gene molecular biomarker panel that can identify TNBC patients who have DTCs in their BM and who have a high risk of cancer recurrence. In this project, we will isolate and further characterize the genetics of individual DTC cells from TNBC patients, to better understand how to develop new therapies to eliminate them and prevent metastatic disease. We will also examine whether and how a patient’s own immune cells contribute to the survival of DTCs in the BM. Importantly, we will conduct a pilot clinical trial to determine whether altering the function of immune cells in TNBC patient BM can help eliminate these tumors cells and prevent future metastatic tumor recurrence. Overall, these studies are geared to discover novel therapeutic strategies to eliminate DTCs and potentially improve long-term survival in patients with TNBC.
Principal Investigator: Simon Haroutounian, PhD, MSc Goal: To determine if lidocaine can reduce the occurence and severity of oxaliplatin-induced peripheral neuropathy, a painful common side effect of chemotherapy. Description: Colorectal cancer is the second leading cause of cancer-related death in the US. Oxaliplatin is a key chemotherapy agent demonstrating improved survival in colorectal cancer, but causes injury to sensory nerves in 72% of patients receiving treatment. This nerve damage, called peripheral neuropathy (PN), can cause substantial pain, numbness and sensory changes like extreme sensitivity to cold. PN leads to dose reduction or early discontinuation of oxaliplatin in 50-70% of patients, reducing patient survival by 5-14 months. In approximately 20% of patients, oxaliplatin-induced PN persists for months or years after chemotherapy. The study aims to determine whether intravenous lidocaine can reduce the incidence and the severity of oxaliplatin-induced PN. In a prospective, randomized study, patients with colorectal cancer will receive lidocaine or placebo with their standard-of-care oxaliplatin-based chemotherapy. The key outcomes, compared between the groups, include: 1) symptoms and signs of peripheral neuropathy, 2) cumulative dose of oxaliplatin, and 3) adverse effects.
Principal Investigator: Julie Schwarz, MD, PhD Goal: To explore why obese patients treated with radiation therapy for cervical cancer have better response rates than patients who are not obese with the ultimate goal of identifying a dietary supplement or drug that can be given to patients to promote better treatment responses. Description: Many patients struggle with obesity, and studies have shown that obese cancer patients treated with surgery and chemotherapy have poor outcomes. Surprisingly, we have found that obese patients treated with radiation therapy for cervical cancer are cured more often than patients who are not obese. Obese patients have increased body fat and circulating levels of fats. In the laboratory, we have shown that free fatty acids enhance the effects of radiation. After radiation treatment, cancer cells actively take up fatty acids, and this results in changes in cell signaling that promote tumor cell death. In this grant, we will perform additional experiments in cells and animal models to understand how free fatty acids and obesity are promoting the response to radiation therapy. Our ultimate goal is to identify a dietary supplement or drug that we can give to patients that will promote treatment sensitivity.
Principal Investigator: Yin Cao, ScD, MPH Goal: To better understand the relationship between bacteria in one’s oral cavity and their future risk of developing Barrett’s Esophagus and Esophageal Adenocarcinoma. Description: In the US, esophageal adenocarcinoma (EAC) has had a nearly seven-fold increase in incidence over the last four decades. However, EAC is highly lethal compared to other cancers in that 80% of EAC patients would die within 5 years. The prevention and early detection of EAC and Barrett’s esophagus (BE), the established premalignant lesion of EAC, is a high clinical priority and research challenge. Bacteria and/virus may be important to this disease process but studies are limited. Project 1 will for the first time examine bacteria in the oral cavity and how that relates to future risk of BE in two large studies which have followed initially healthy population for over 30 years. Project 2 will look into whether we could detect viruses in the saliva samples collected from the above studies, as well as from esophageal samples collected from BE patients in a large hospital based cohort. The two projects will provide novel knowledge on BE/EAC development.
Principal Investigator: John Welch, MD, PhD Goal: To determine if two existing acute myeloid leukemia (AML) drugs are more effective when administered in combination with each other using mouse and human models. Description: This project focuses on completing the required pre-clinical studies needed to translate a benchtop observation into a clinical trial in acute myeloid leukemia (AML). We found that two old drugs (all-trans retinoic acid and bexarotene) exhibit strong synergy when added together in a mouse model of AML, whereas they have very modest activity by themselves. Both drugs are FDA approved, are orally available, and have well-characterized and tolerable side effects. In this proposal, we will determine whether this combination is highly active in other mouse and human models of AML, or if these drugs are only active in this one mouse model of AML (MLL-AF9). In addition, we will work with medicinal chemists at Washington University to make multiple subtle changes in the chemical structure of bexarotene, and determine whether any of these changes augment the synergistic interaction and could improve on bexarotene as anti-leukemic agents. These results will form the justification for future clinical trials in AML.
Pilot implementation and feasibility assessment: Multilevel intervention to reduce rural colon cancer disparities
Principal Investigator: Aimee James, PhD, MPH Goal: To develop a multi-level intervention in order to improve colon cancer screening and follow-up in primary care clinics in rural Southern Illinois. Description: Rural areas in the Midwest face higher rates of colon cancer mortality. Screening can help reduce the burden, but screening rates are relatively low in rural areas. Further, many people who get screened do not receive appropriate diagnostic follow-up, especially if they were screened with fecal testing. Better and more consistent implementation of strategies that we know can be effective can help under-served communities increase screening and improve follow-up of abnormal cancer screening tests. Interventions at multiple levels are critical to success, as intervening on patients or primary care providers alone is unlikely to have substantial impact. We have partnered with a rural healthcare system (Southern Illinois Healthcare) to develop a multi-level intervention using evidence-based strategies to improve screening and follow-up in primary care clinics in rural Southern Illinois. The preliminary research proposed here will strengthen our submission of our NCI grant to test the effectiveness of our intervention.
Principal Investigator: Milan Chheda, MD Goal: To understand how a gene (ZFHX4) contributes to the treatment-resistant state of glioblastoma. This information will help us develop new treatments for brain tumors. Description: Glioblastoma is the most common and aggressive primary brain tumor. A major problem is that despite therapy, the cancer inevitably and quickly recurs. We have identified a gene, ZFHX4, which is required for this treatment-resistant state of glioblastoma cells. Here, we will dissect the possibilities of how ZFHX4 does this. Our studies will test how ZFHX4 operates in patient tumors, how it responds in the setting of treatment, and whether it works alone to cause brain tumors or cooperates with other genes. These findings will help us understand how we can better target and kill the most treatment-resistant cells in these devastating brain tumors.
Principal Investigator: Tahir Rahman, MD Goal: To gather and analyze a large data set of women who have taken antipsychotic and mood stabilizing drugs to determine which drugs are associated with an increased rate of breast cancer. Description: Breast cancer is the most common cancer among women in the United States. Medications called antipsychotics and mood stabilizers are used to treat millions of patients worldwide for a variety of mental health issues such as mood disorders and psychosis in girls and women. Antipsychotic drugs often artificially raise levels of a naturally occurring hormone called prolactin in the body. High prolactin levels have been linked to the development of breast cancer in some studies. This study will examine millions of women who have taken antipsychotic and mood stabilizing drugs to determine which drugs are associated with an increased rate of breast cancer. The results of this study will allow doctors to make better treatment guides to protect girls and women from developing breast cancer.
Principal Investigator: Ryan Teague, PhD, Saint Louis University Goal: To understand how obesity influences immunotherapy treatment outcomes for cancer patients and provide fresh insight for improved treatment options for all patients. Description: Over a third of Americans are considered obese, a condition associated with impaired immunity and a higher risk of cancer. But cancer treatments have changed dramatically in recent years, shifting toward strategies of immunotherapy that rely on boosting a patient’s own immune system to fight cancer. We hypothesize that obesity limits the success of immunotherapy, which is supported by research in our lab and others using animal models. Whether obesity influences outcomes in human cancer patients remains unclear and has been mired by conflicting clinical results. These inconsistencies have contributed to the controversial “obesity paradox”, which suggests that obesity has a neutral or even positive impact on patient outcomes, but this idea has come under intense scrutiny. We have proposed new mechanistic studies in animal models and complementary analysis of human tissues from cancer patients to demystify this controversy and provide fresh insight for improved treatment options in all patients.
Principal Investigator: Brian Van Tine, MD, PhD Goal: To test a therapy based on cancer cell metabolism that causes tumor starvation in a clinical trial in rare tumors called sarcomas. Description: The goal of this proposal is to test a therapy based on cancer cell metabolism that causes tumor starvation in a clinical trial in rare tumors called sarcomas. Arginine is a crucial building block needed by both normal and cancerous cells. While normal cells can make their own arginine, we have discovered that sarcomas do not have the ability to make their own. As a result, when we use a drug that destroys arginine in the bloodstream, we are able to selectively starve tumors, as normal cells are able to make arginine and survive. We have found that when tumors are in this starvation state, they are more responsive to chemotherapy. Therefore, we propose to test this finding in a Phase II clinical trial in sarcoma patients. In addition, we will continue to study the effects of arginine starvation in the laboratory-based models. Taken together, we will harness our unique findings in tumor metabolism to improve the care of sarcoma patients.
Principal Investigator: Alessandro Vindigni, PhD, Saint Louis University Goal: To study how ovarian cancers carrying BRCA1-gene mutations cope with chemotherapy treatment preventing cell death and ultimately develop a new strategy for chemotherapy. Description: Mutations in the BRCA1 gene are associated with several forms of cancer, including breast and ovarian cancers. Cancer patients carrying BRCA1-gene mutations are often treated with chemotherapeutics that damage the cancer cell’s DNA in the attempt to stop replication and induce cancer cell death. To better mimic chemotherapy in patients, we developed an approach to treat cancer cells with multiple doses of DNA-damaging chemotherapeutics to understand how cancer cells respond. In doing so, we found that BRCA1-mutant cancer cells can adapt to these multiple-drug doses by turning on a rescue pathway as a last resort to protect their DNA replication and prevent cell death. This pathway relies on a specialized protein (called PrimPol) and is only activated in BRCA1-mutant cancer cells, but not in normal cells. The goal of this project is to define how this rescue pathway works and to provide a new strategy to sensitize BRCA1-deficient tumors to chemotherapy drugs by preventing cells from using this rescue pathway.
Principal Investigator: Delphine Chen, MD and Andrea Wang-Gillam, MD Goal: To develop a new PET imaging tool to more accurately identify when pancreatic cancers would benefit from the addition of a PARP inhibitor (an emerging anticancer therapy) to standard chemotherapy. Description: Pancreatic cancer has poor treatment outcomes due to the fact that nearly all patients develop chemotherapy treatment-resistant disease. Imaging methods that can help study the causes of treatment resistance and provide information regarding what type of therapy could help overcome the treatment resistance could lead to transformative advances in treating this disease. We propose developing a new PET imaging tool to image the expression of PARP, a protein involved in DNA repair, that can more accurately identify when pancreatic cancers would benefit from the addition of a PARP inhibitor (an emerging anticancer therapy) to standard chemotherapy than currently available assays. This is especially important for pancreatic cancer patients, for whom few effective treatments exist and, of those treatments, treatment-related toxicities are severe. Our approach will enable clinicians to identify pancreatic patients who are likely to response to PARP inhibitors, thus improving outcomes while reducing unnecessary toxicities.
Principal Investigator: Cynthia Ma, MD, PhD and Jason Held, PhD Goal: To understand the importance that two enzymes have in triple-negative breast cancer (TNBC) growth and their roles in causing resistance to different chemotherapy drugs used for treating TNBC. Description: Resistance to chemotherapy is a major cause of death in patients with breast cancer. There is a significant unmet clinical need to develop treatments that improve the effectiveness of chemotherapy by preventing the cancer cells’ ability to become resistant to the treatment. We conducted a study in mice who had human breast cancer cells grafted to their bodies (called patient-derived xenografts, or PDX models). This study was done to determine what molecules are causing resistance to cancer therapy and learn how they work and interact with each other inside breast cancer cells. We identified a new process that allows breast cancer cells to become resistant to chemotherapy. Interrupting this process stops cells from dividing and makes them more sensitive to chemotherapy. We found that high levels of enzymes (called NEK9 or MAP2K4) are associated with a higher chance of cancer recurrence in patients with triple-negative breast cancer (TNBC), which is a more aggressive type of breast cancer with a high risk of coming back after treatment. In this proposal, we plan to learn more about how these enzymes work by conducting experiments in breast cancer cells and PDX models. We will test their importance and roles in making TNBC cancer cells grow, and determine which type of chemotherapy could be effective in keeping this process from helping breast cancer cells grow. Lastly, we will examine whether high levels of enzyme activity is associated with resistance to chemotherapy in TNBC patients using samples obtained from patients who have all been treated with the same type of chemotherapy during their participation in an existing clinical trial. The long-term goal of this research is to develop a new treatment approach for TNBC which lowers the levels or activities of these enzymes to improve the effectiveness of chemotherapy, reduce the chance of recurrence, and improve patient outcomes.
Principal Investigator: Josh Rubin, MD, PhD; Joseph Ippolito, MD, PhD; and Liu Lin Thio, MD, PhD Goal: To perform a first-in-kind clinical trial to determine whether a ketogenic diet can improve outcome when combined with chemotherapy for children with recurrent brain tumors. Description: Survival for children with recurrent brain tumors is dismal and there is a desperate need for new ways of thinking about treatment, and better use of currently available therapies. This project seeks to do both by targeting brain tumor metabolism, a recognized but still immature approach to treatment. Cancerous growth requires adaptations in cellular metabolism. There is a large increase in sugar metabolism in particular, which is likely to constitute an Achilles heel for cancer cells. Here, we will perform a first-in-kind clinical trial to determine whether starving cancer cells of sugar with a ketogenic diet can improve outcome when combined with chemotherapy for children with recurrent brain tumors. This trial could establish St. Louis Children’s Hospital and Washington University as pioneers in the development dietary approaches to cancer treatment.
Principal Investigator: Grant Challen, PhD Goal: To understand how mutant stem cells react to specific signals from the bone to become leukemic cells, and to identify methods to eliminate the mutant cells before they can cause cancer. Description: As we age, the stem cells that generate the blood and bone marrow accumulate genetic mutations. Some of these mutations occur in cancer-causing genes, which allow the mutant cells to overtake the bone marrow. We recently showed that virtually all people over 50 have at least one stem cell with a cancer-associated genetic mutation. This observation has led us to the question – if these mutations are happening in our bone marrow all the time as we age, why doesn’t everybody eventually develop cancer? We propose that specific signals from the bone are required for these mutant cells to generate cancer, and have identified a component of the natural inflammatory response that promotes survival of stem cells with cancer-causing mutations. The goal of this project is to understand how mutant stem cells react to this signal, and to identify methods to eliminate them before they can cause cancer.
Principal Investigator: Jaebok Choi, PhD Goal: To determine how two proteins (IFNgR and IL6R) cause graft-versus-host disease (GvHD) after a bone marrow transplantation in leukemia patients, and to test whether drugs that inactivate these two proteins can prevent GvHD without interfering with the killing of leukemia cells. Description: The most effective treatment for many patients with leukemia or other blood cancers is to administer bone marrow transplants containing immune cells obtained from a healthy donor whose immune system is closely matched and thus should not “see” the cancer patient’s body as foreign and thus should not attack it. Although these cells can effectively kill the patient’s cancerous cells, in ~50% of patients the donor cells still attack the patient’s skin, intestines, lung, and liver in a phenomenon known as graft-versus-host disease (GvHD) because it recognizes the patient as “foreign”. GvHD can be severely debilitating or even fatal and is the primary obstacle to successful transplantation. We have identified two proteins (IFNgR and IL6R) that cause GvHD. We have also demonstrated that genetically inactivating these proteins eliminates GvHD, yet the healthy immune cells can still kill the leukemia cells in mouse models. In this proposal, we will determine how these proteins cause GvHD and test whether drugs that inactivate these proteins prevent GvHD without interfering with the killing of leukemia cells. Such drugs would revolutionize bone marrow transplantations, enhance patient’s quality of life, and improve survival.
Principal Investigator: David DeNardo, PhD Goal: To gain an understanding of how to target a subset of immune cells that are responsible for creating a scar-like “armor” thought to protect pancreatic cancer cells and ultimately improve outcomes for pancreatic cancer patients. Description: Pancreatic cancer has a dismal prognosis with only 8% of patients living past five years. One of the major challenges to treating pancreatic cancer is that current therapies such as chemo- or radiation therapy are not as effective in pancreatic cancer compared to other cancers. This difference may be due to the unique environment in which pancreatic cancer cells reside. The pancreatic tumor environment closely resembles highly fibrotic scar-like tissue. This scar-like environment is thought to provide a biological “armor” for pancreas cancer cells to survive and even thrive in during therapy. Thus, new drugs that can break through this this scar-like “armor” would be highly desirable as treatments of pancreatic cancer. We have discovered a unique subset of immune cells, called macrophages, which create this scar-like “armor”. Thus, we believe these immune cells represent an excellent therapeutic target. However, the classical assumption is that macrophages in tumors come from the bone marrow. Based on this assumption several ongoing clinical trials are targeting macrophage through their recruitment from blood. However, we have found that the macrophages that regulate the scar-like “armor” of pancreatic cancer are ancient cells that entered the pancreas during development of the fetus and the rules that govern their growth are different than those that come from the bone marrow. Thus, these studies will seek to understand how to target this subset of macrophages to improve outcomes for pancreatic cancer patients.
Principal Investigator: Gavin Dunn, MD, PhD Goal: To develop a better understanding of how the immune system recognizes brain tumors and to find a way to study immune response to recurrent tumors. Description: Glioblastomas are the most aggressive brain cancer with an average survival of 15 months. Although successful in other cancers, treatments that harness the immune system to fight tumors—or, immunotherapies—are not yet as effective in glioblastoma. Some key barriers include our limited understanding of immune responses to brain tumors when they first form and when they come back after standard treatment. In fact, recurrent tumors should be more responsive to immunotherapies because they contain major genetic changes that make them more susceptible to immune attack. Indeed, one could liken this to the removal of a disguise, these genetic changes should allow the immune system to “see” the tumor cells but the immune system does not kill the tumor cells. The major question is given the fact that the immune system is designed to kill these cells, why doesn’t it do so? These question is difficult to study using current brain tumor lab models. Our goal is to use a new lab model of brain cancer in mice that we developed to better understand how the immune system recognizes brain tumors and to find a way to study immune responses to recurrent tumors. This work will help shape how we can enhance immunotherapies for glioblastoma patients.
Principal Investigator: Kristen Naegle, PhD (Danforth Campus) Goal: To uncover an important basic phenomenon that occurs within normal cell biology and gain a better understanding of the role it plays in the development of cancer cells. Description: Controlling where proteins are in the cell is vital to whether they perform the right function in the right place. There is a large class of proteins in human cells (lipid-binding proteins) that get recruited to the right place because they can interact with lipids found on the surfaces of the cell and many structures within the cell (i.e. membranes). This project will test a novel idea that a normal chemical process that occurs within cells (protein modification) can control the interaction of lipid-binding proteins with lipids in cell membranes. To test this idea, we will compare lipid-binding protein interactions with lipids before and after protein modification. These modifications may prevent proteins from properly interacting with cell membranes and prevent the correct placement of proteins within cancer cells, since increased amounts of protein modifications on lipid binding proteins are often found in human cancers. We hope to uncover an important basic phenomenon of normal cell biology and better understand the role protein modifications have in cancer. This could ultimately identify new ways in which therapeutics could target and kill cancer cells.
Principal Investigator: Jacqueline Payton, MD, PhD Goal: To better understand and provide critical insight into the role that a newly discovered class of RNA molecules have in the development of Non-Hodgkin Lymphoma. Description: Non-Hodgkin lymphoma (NHL) is the most common blood cancer in the U.S. Half of all Lymphoma patients have disease that is resistant to current treatments; thus there is an urgent and unmet need for new therapeutic approaches. Our limited understanding of the biological changes that contribute to lymphoma progression is a major obstacle to developing new treatments. To address this critical knowledge gap, we analyzed over 100 human Lymphoma patient samples and normal samples. Our preliminary experiments highlighted a new class of molecules called lncRNAs as likely drivers of Lymphoma development. These studies will determine the function of the top 3 Lymphoma lncRNAs, and how they contribute to cancer growth and survival. At the completion of these studies, we expect to provide critical insight into Lymphoma disease and the potential to discover new therapeutic targets.
Principal Investigator: Lukas Wartman, MD Goal: We will characterize how the inactivation of the gene KDM6A can cause specific changes that drive acute myeloid leukemia. Description: KDM6A is a gene that controls how many other genes are turned on or off, and it is frequently mutated in many types of cancer, including leukemia. KDM6A mutations are thought to cause changes in the expression of other genes that can potentially act as important drivers of leukemia (and cancer in general). In this proposal, we will identify the specific gene expression changes that are associated with the loss of KDM6A activity in leukemia cells and define how these changes are involved in leukemia development. We will also test the ability of drugs that act in the same pathway as KDM6A to treat mouse models of human leukemia. These studies may reveal new approaches for the treatment of leukemia patients, who still usually die from complications of their disease.
Principal Investigator: Buck Rogers, PhD and Dong Zhou, PhD Goal: Multi-PI Pre-R01 Recommendations. To determine how a modified FDA-approved agent that targets prostate cancer cells goes about killing the prostate cancer cells and optimize the amount of drug that is needed to cure mice with prostate tumors. Description: Late stage prostate cancer is a highly lethal disease with no curative therapeutic options. Recently, the FDA approved a radioactive drug that has increased the survival of late stage prostate cancer patients. This drug is effective even though it is not delivered to the prostate cancer cells themselves, but to normal cells near the prostate cancer. We have developed a drug similar to this FDA-approved agent, but it is targeted to the prostate cancer cells, which should make it much more effective than the FDA-approved agent and with fewer side effects. We have preliminary data from studies involving mice with prostate cancer indicating this approach will work. Through this Siteman Investment grant, we will determine how our drug kills cancer cells and optimize the amount of drug that is needed to cure mice with prostate tumors. This data is needed to be competitive for NIH funding and other external grants.
Role of Interferon Regulatory Factor 4 in Human T Cell Leukemia Virus-Associated Adult T Cell Leukemia Lymphoma
Principal Investigator: Lee Ratner, MD, PhD Goal: To understand the role of IRF4 in adult T-cell leukemia lymphoma which will have applications in deciphering its role in other cancers, including multiple myeloma and lymphoma, and developing novel treatment approaches. Description: Human T-cell leukemia virus type 1 is the cause of a refractory T cell cancer, adult T-cell leukemia lymphoma (ATL). This project is based on exciting new data that mutations are common in genes that code for a pathway that allows the T cell receptor to induce cell growth. Notably, we found that one of these components, interferon regulatory factor 4 (IRF4) is overexpressed in almost all cases, as a result of IRF4 gene mutation and/or amplification, or mutation of genes in the pathway upstream of IRF4. We will determine in tissue culture and mouse models the effect of IRF4 overexpression on T cell growth and proliferation. In future studies, we will examine in mice the effects of IRF4 inhibitors on ATL growth. Overall, these studies have the potential to lead to an important clinical advance in ATL treatment, which could have applications in other leukemias or lymphomas.
Principal Investigator: Amit Pathak, PhD Goal: This project will investigate whether invasive breast cancer cells remember their primary tumor environment even after they escape to healthy tissue. Description: The relentless progression of metastasis is driven by the ability of cancer cells to thrive in distinct tissues and organs. This seamless adaptability of cancer cells to new environments is recognized as ‘plasticity’. However, it remains unknown whether the invasive cancer cells store any memory of past environments. The central hypothesis of this proposal is that breast cancer cells store a mechanical memory of their past environment through discrete memory-storing signals. Inhibition of this memory-storing signaling could negate the mechanical priming of cancer cells by their primary breast tumor. We will develop innovative devices that integrate multiple steps of the breast tumor invasion trajectory. This is a necessary first step towards strategies to modulate the storage of the tumor memory in escaped breast cancer cells. The knowledge of memory-storing signaling targets in breast cancer cells may open new avenues for therapeutics by altering their ability to invade through healthy tissue.
Principal Investigator: Michael Rettig, PhD Goal: The long-term goal of this proposal is to develop a new method to harvest healthy blood stem cells from the bone marrow of donors to use as transplants for patients with leukemia. In addition to mobilizing healthy stem cells from donors, this new method may also be useful in getting leukemia cells out of the bone marrow and into the blood where they will be more sensitive to killing by chemotherapy drugs (chemosensitization). Description: The only curative therapy for many patients with blood cancers and bone marrow failure is to administer transplants of healthy blood stem cells derived from the bone marrow of a donor. This process is called hematopoietic stem cell transplantation (HSCT). One key obstacle to the broader success of HSCT is collecting a sufficient number of blood stem cells to create an effective transplant. In this proposal we are developing a new method to rapidly and efficiently harvest healthy stem cells from the blood of donors using two drugs that have never been combined before. One drug detaches the stem cells from the bone marrow while the second drug not only detaches the stem cells from the bone marrow but also helps them exit the bone marrow and enter the blood stream (i.e., stem cell mobilization) where we can collect them. This novel stem cell mobilizing procedure is expected to shorten the time required for donors to donate stem cells, significantly reduce costs, and increase the utility of stem cell transplantation. Our novel stem cell mobilization procedure may also root out leukemia cells from the bone marrow environment where they are protected from chemotherapy and move them into the blood where they should be sensitive to the effects of cytotoxic chemotherapy, a process called chemosensitization.
Principal Investigator: Jianguo Liu, MD, PhD Goal: One major problem about cancer, including breast cancer, is that cancer cells grow uncontrollably. Our goals are to find out the reasons that cause the unstoppable growth of cancer cells, with a focus on the role of a new protein named MCPIP1. Description: We recently found that a new protein named MCPIP1 (Monocyte Chemotactic Protein Induced Protein-1) plays an important role in control of breast tumor growth. We found that low MCPIP1 levels in tumors were strongly associated with poor survival of breast cancer patients over 13 years follow up after surgical, namely low MCPIP1 is bad for breast cancer patients. When we expressed MCPIP1 in tumor cells, tumor cells were dead and tumors were disappeared in animal study. We think MCPIP1 is a powerful new target for breast cancer treatments. In this study we plan to study how MCPIP1 suppresses breast tumor growth, why MCPIP1 levels are lower in tumor cells, and what are the drugs that can induce MCPIP1 in breast tumor cells. The results of this study will provide us with the basis to use MCPIP1 as a new breast cancer treatment.
Principal Investigator: Joel Garbow, PhD; Keith Rich, MD; and, Christina Tsien, MD Goal: To develop a greater understanding of the factors that affect the growth of recurrent glioblastoma and, ultimately, develop novel therapies to treat this incurable tumor. Description: Glioblastoma remains the most common malignant brain tumor. Despite state-of-the-art treatment, including surgery, chemotherapy, and radiation, these tumors are incurable. Inevitably, the vast majority will recur, becoming more aggressive and invasive in the process. The goal of this work is to develop: i) a greater understanding of the factors that affect the growth of recurrent tumor and ii) novel therapies. Using a novel animal model of recurrent tumor developed in our laboratory, we will test optimal treatment strategies. We will explore advanced imaging techniques to non-invasively identify tumor and assess early treatment responses, using methods that can be easily translated into the clinic. We will also study how the molecular properties of tumors change in response to radiation therapy, and how these changes affect the way that the body’s own immune system, either alone or supplemented with additional therapies, is able to fight off the growth of recurrent tumor.
Principal Investigator: Roberta Faccio, PhD and Roberto Civitelli, MD Goal: To define the phenotype of “bone-like” stromal cells and how they affect tumor growth and metastasis which may ultimately assist doctors in determining cancer severity and devise new anti-cancer treatments. Description: Working in mouse models of tumors, we have discovered that some cells in breast, lung, or skin tumors have features that are normally seen only in bone cells. These “bone-like” cells are also present in small numbers (about 3%) in some tissues (lung, breast, skin) of normal mice; but their numbers increase several-fold when tumor cells are injected in the mouse, and, remarkably, they pass into the blood stream when tumors are present. We also find this ectopic “bone-like” cells enhance tumor growth. We hypothesize that these “bone-like” cells are part of the body’s response to a tumor to facilitate tumor initiation, growth and metastasis. The proposed research will define the phenotype of these cells, and how they affect tumor growth and metastasis. Results may impact future patient care, as the presence of these cells might tell doctors about the severity of cancer, and may help us devise new anti-cancer treatments.
Principal Investigator: Jason Mills, MD, PhD Goal: To identify the genes may start cancers in the stomach, intestines, liver and pancreas to find drugs targeting those genes to stop cancer before it starts. Description: Cancers of the colon, liver, pancreas and stomach are among the most common and deadliest in the world. Because these cancers first show pre-cancerous changes, such as intestinal polyps, preventing or even reversing these cancers may be possible if we understood how they begin. This research will study genes and cell-to-cell communication that breed pre-cancerous growths. We are then working towards finding therapeutic drugs to work with individual patients’ genes to block onset of cancer.
Principal Investigator: John F. DiPersio, M.D., Ph.D. Medicine, Pathology and Immunology, Pediatrics Goal: To generate optimal CAR-T for targeting T cell malignancies and to test the efficacy of pharmacologic and genetic approaches to mitigate CAR-T mediated cytokine release syndrome (CRS) while maintaining robust anti-leukemic activity. Description: T cell leukemias and lymphomas represent a class of devastating cancers with high rates of relapse and mortality in both children and adults for which there are currently no effective or targeted therapies. Despite advances in Chimeric Antigen Receptor (CAR)-T cell immunotherapy for B cell malignancies, several challenges have limited development of CAR-T against T cell malignancies. This is primarily due to the shared expression of antigens on normal T cells and malignant cells. We used gene editing to develop an ‘off-the-shelf’ CAR-T product against T cell acute lymphoblastic leukemia (T-ALL) that does not have the risk of CAR-T cells attacking each other or non-cancer cells in the patient. This proposal is aimed at further optimizing CAR-T to treat T cell malignancies as studied using pre-clinical models. Additionally, we will develop therapeutic strategies to overcome life-threatening cytokine release syndrome (CRS), the major limitation of adoptive T cell immunotherapies in general.
Principal Investigator: Kendall Blumer, PhD, a professor of cell biology and physiology at the School of Medicine and a research member of Siteman Cancer Center Description: Uveal melanoma (UM) is the most common tumor within the eye in adults. Nearly half of UM patients develop metastatic disease with mean overall survival of 6-12 months. Rates of metastatic disease and mortality are unchanged by treating primary tumors, and proven therapies for metastatic UM do not exist. A major roadblock is the absence of therapies that inhibit the tumor cell-driving proteins in UM. This project describes the first pharmacological approach toward targeted therapy in UM. It uses compounds that specifically inhibit the tumor cell-driving proteins in UM. It will determine whether these compounds provide leads toward first-in-class, targeted therapeutics by analyzing their effects on patient-derived UM tumor samples and in mouse models of UM. Studies of these inhibitors could lead eventually to the first true therapeutic breakthrough in metastatic UM.
Principal Investigator: Ron Bose, PhD, MD, an associate professor of medicine at the School of Medicine and a research member of Siteman Cancer Center Description: Metastatic breast cancer causes 40,000 deaths per year in the U.S. We identified HER2-activating mutations (HER2mut) as an uncommon but highly treatable mutation in metastatic breast cancer, and we have successfully performed a multi-institutional, phase II clinical trial treating HER2mut metastatic breast cancer patients with the HER2 tyrosine kinase inhibitor, neratinib. Several key observations were made from this clinical trial, including the fact that more than 90 percent of the HER2mut metastatic breast cancer patients had estrogen receptor-positive breast cancer. We will study neratinib-based drug combinations using two types of mouse models of HER2mut breast cancer. This research will enable the next line of clinical trials for HER2mut metastatic breast cancer patients.
Principal Investigator: Christopher Maher, PhD, an assistant professor of medicine at the School of Medicine, an assistant director at The McDonnell Genome Institute and a research member of Siteman Cancer Center Description: Colorectal cancer is the most common gastrointestinal cancer in the U.S., with about half of patients developing advanced disease. Of them, more than 80 percent will succumb within 5 years. This represents an unmet clinical need to improve the current inadequate treatments. Currently, our limited understanding of the ways in which the original colon tumor spreads throughout the body, or metastases, is a critical barrier for improved treatment. To address this, we studied primary tumors and their metastases from the same patient to discover a new class of molecules involved in metastasis called lncRNAs. Based on our preliminary data, we will study a promising lncRNA acting as a “master regulator” by interacting with specific proteins to alter their normal function and cause the tumor to spread. Later, we intend to evaluate methods to inhibit, or “drug,” this lncRNA, ultimately leading to the development of novel therapeutics for improving outcomes in this dedrugadly disease.
Project: Functional Regulation of DNA Damage Response by the Ubiquitin-selective Protein Segregase VCP
Principal Investigator: Jieya Shao, PhD, an assistant professor of medicine at the School of Medicine and a research member of Siteman Cancer Center Description: Chemotherapeutic resistance is a huge clinical problem facing both oncologists and cancer patients. As such, we urgently need to understand the resistance mechanisms and develop predictive biomarkers for both treatment response and chemo-sensitizing methods. One way cancer cells resist chemotherapy is by increasing their ability to repair treatment-induced DNA damage. This depends on the coordinated actions of DNA repair proteins and their dynamic, timely assembly and disassembly at the damage sites. With this grant, we will investigate VCP, a protein known to facilitate the timely removal of repair factors from DNA during damage response. Specifically, we will focus on a phosphorylation event of VCP that is induced by DNA damage and whose level inversely correlates with breast cancer outcome. Based on preliminary data, we hypothesize that VCP phosphorylation plays an important role in DNA damage response and may greatly influence cancer cell response to genotoxic chemotherapies. The experiments are designed to test this hypothesis. If successful, they will rationalize future investigation of the clinical value of phospho-VCP as a predictor of cancer chemotherapy response and a novel target of chemo-sensitization.
Principal Investigator: Tanya Wildes, MD, an assistant professor of medicine at the School of Medicine and a research member of Siteman Cancer Center Description: Each year, one in three older adults falls. Older adults with cancer are at even greater risk; as many as half fall every six months. This may be due to medications that cause unsteadiness, weakness, treatment side effects, and nerve damage from chemotherapy, but exactly which risk-factors are most important is not known. It is also unknown how risk changes over time in older adults receiving cancer treatment. In this study, we will follow 200 older adults receiving cancer therapy for 6 months to determine risk factors for falls. The ability to identify people at greater risk for falls, coupled with another current project adapting a fall-prevention intervention for older adults with cancer, will provide the necessary elements to conduct a clinical trial of a fall-prevention intervention, tailored to the needs of older adults with cancer, and targeted to those at greater risk.
Principal Investigator: Jeffrey Bednarski, MD, PhD, an assistant professor of pediatrics at the School of Medicine and a research member of Siteman Cancer Center Description: Pre-B acute lymphoblastic leukemia (ALL) is the most common cancer in children. However, remarkably little is known about the basis of the initiation and maintenance of this leukemia. During normal development, immune cells rely on signaling from surface receptors to drive cell growth and generate a diverse immune response. Pre-B leukemic blasts have errors in the signaling from these receptors that supports their uncontrolled growth and survival. Thus, these signals must be carefully balanced to support normal immune cell growth but prevent transformation into leukemia. We have identified a novel mechanism that controls surface receptor signaling in immune cells. Our goals are to understand how this signaling circuit is coordinated to direct early B cell development and how corruption of this pathway leads to leukemia. We expect that these studies will provide important insights into the development of leukemia and will identify novel therapeutic targets in pediatric ALL.
Principal Investigator: Sergey Korolev, PhD, an associate professor of biochemistry and molecular biology at Saint Louis University School of Medicine and a research member of Siteman Cancer Center Description: We propose to study how mutations in the BRCA2 and PALB2 tumor suppressor proteins lead to cancer and the development of drug resistance during cancer treatment. We will study how these proteins normally work in the cell to repair broken chromosomes, and evaluate the disease-causing potential of mutations to one or both of these proteins. In addition, we will isolate BRCA2 and PALB2 to discover inhibitors of these proteins, which can be used to improve the effectiveness of anticancer therapies and also could be used to discover alternative treatments for the diseases caused by these mutations.
Principal Investigator: James Skeath, PhD Description: Metastatic spread of tumors is often the key event that leads to cancer-related mortality. Although the blood and lymph systems represent the most common routes for tumor metastasis, nerves identify a key under-appreciated path for cancer spread. Perineural invasion is the process by which tumor cells migrate along nerves to invade distant tissues. First identified in the 1800’s, perineural invasion is common in many cancers and a marker of poor outcome. Despite its clinical significance, the causes of perineural invasion remain unknown. We have developed one of the first in vivo model systems of perineural invasion. Here, we will exploit this system to uncover the molecular causes of perineural invasion. Given the lack of knowledge about perineural invasion, our research holds the potential to break open the field and catalyze advances in our understanding of this poorly understood form of cancer metastasis.
Principal Investigator: Steven Teitelbaum, MD Description: Liver metastasis is among the most common causes of death among women with breast cancer. Once liver metastasis has occurred there is an 80% likelihood of dying within two years. Any strategy which reduces liver metastasis would, therefore, have a profound effect on breast cancer survival. The United States is experiencing an epidemic of obesity which is often associated with fatty liver disease, estimated to be present in 20-30% of Americans. Surprisingly, nothing is known about the influence of fatty liver disease on liver metastasis. We find that whereas normal mice are resistant to liver metastasis of breast cancer, those with fatty liver are predisposed. This observation is important as fatty liver disease is reversible. We propose to determine why fatty liver predisposes to liver metastasis and if reducing liver fat prevents cancer spread. If our data extends to humans, it would have significant public health implications.
|Principal Investigator: Zhongsheng You, PhD Description: The mainstays of cancer treatment have been radiation and chemotherapy that generate DNA damage. However, the efficacy of DNA-damaging therapies is hampered by serious side effects and frequent cancer relapse. A major cause of cancer relapse is the alterations in gene expression that occur after treatment in the cells in the environment surrounding a tumor. Thus, it is imperative to understand the molecular mechanisms for the gene expression changes induced by DNA damage. The goal of this pre-R01 application is to explore the role of an RNA degradation pathway called nonsense-mediated mRNA decay in the reprogramming of gene expression in response to DNA damage. This project is expected to generate key experimental results that will enable development of new therapeutic strategies targeting harmful changes in the tumor environment.|
Principal Investigator: Nima Mosammaparast, MD, PhD Description: Alkylating agents- a highly reactive group of molecules- are frequently used in cancer chemotherapeutics. These drugs are thought to work primarily by damaging the genome, which consists of DNA. However, another key molecule in the cell that is targeted by these drugs is RNA. Yet, we do not understand whether RNA damage by alkylating agents is important for tumor responses to these drugs. At a chemical level, RNA is very similar to DNA and changes to its structure often affect its function during protein synthesis. Therefore, we propose that RNA damage contributes to cell death upon exposure to alkylating agents. Our studies will focus on understanding how cells deal with RNA damaged with alkylating agents, and how this may affect tumor responses to these commonly used drugs. This work represents a major paradigm shift in our understanding of how tumor cells respond to chemotherapy, and may provide new ways of treating multiple types of cancer.
Project: Optimizing Decision Making about Breast Reconstruction after Mastectomy: A Patient-Centered Approach
Principal Investigator: Terence Myckatyn, MD Description: Deciding whether or not to have breast reconstruction after mastectomy, when to have reconstruction, and which type of reconstruction to have is very challenging for patients with breast cancer. Currently, this choice is limited by inadequate information and deficits in knowledge about treatment options. In this proposal, we aim to develop and evaluate a novel clinical decision support tool that integrates patients’ unique clinical characteristics with their preferences to enable clinicians and patients to make high quality breast reconstruction decisions. This research will promote personalized cancer care for patients with breast cancer. Ultimately, this proposal has the potential to improve knowledge of treatment risks, harms, and benefits, enable patients across racial groups to get the treatments they prefer, and improve outcomes patients find important, thereby improving cancer survivorship for women with breast cancer.
Project: Evaluating Cognitive Function and Functional Connectivity in Breast Cancer Survivors Who Received Chemotherapy
Principal Investigator: Jay Piccirillo, MD Description: Chemotherapy has been linked to cognitive impairments among breast cancer patients, especially related to planning, learning, and attention. The neurological basis of this phenomenon, termed CRCI (chemotherapy-related cognitive impairment), is unknown and the impact in patients over extended period of time is lacking. The study aims to establish the groundwork to allow the assessment of the structural brain reasons that CRCI occurs and to evaluate why some patients develop CRCI and others do not. All newly diagnosed eligible breast cancer patients scheduled to undergo chemotherapy at Siteman Cancer Center will be enrolled in order to establish the Clinical Database for Cognitive Assessment. These patients will complete several cognitive function measures pre- and post-chemotherapy. A subset of these patients will complete special MRI functional imaging pre-and post-chemotherapy. Ultimately, the results of this project will support the exploration of the reasons why CRCI occurs and identify ways to improve the survivorship experience for breast cancer patients.
Principal Investigator: William Gillanders, MD Description: Breast cancer is now recognized as a mixed and diverse disease that will require a combination of prevention, diagnostic, and treatment approaches to decrease mortality. While there have been significant advances in treating ER+ and HER2+ disease, Siteman Cancer Center sees 1,100 breast cancer patients per year and many will ultimately succumb to their disease. This Siteman Investment Program Pre-SPORE application brings together a multidisciplinary team of investigators leveraging institutional strengths in basic and translational research. The objective is to obtain NCI funding for a Breast Specialized Program of Research Excellence (SPORE) that will enable rapid clinical translation of basic science discoveries with the goal of impacting patient care. Siteman Investment Program funds will provide critical continuing support for the development of a Breast Cancer SPORE at Siteman Cancer Center with a focus on tumor immunology, oncologic imaging, surgical oncology, and breast cancer prevention.
Project: MRI-guided Laser Heat Ablation to Induce Blood Brain Barrier Breakdown in Pediatric Brain Tumors
Principal Investigator: Karen Gauvain, MD, MSPH, pediatrics; and David Limbrick, MD, PhD, neurological surgery and pediatrics. Description: Researchers take on one of the biggest obstacles to treating pediatric brain tumors: the blood-brain barrier, which keeps chemotherapy drugs from penetrating the brain. A minimally invasive laser procedure, called magnetic resonance imaging-guided laser ablasion (MLA), disrupts the blood-brain barrier in adults, allowing the penetration of chemotherapy drugs into the tumor. The purpose of this study is to examine the outcomes of pediatric brain tumor patients who are treated with MLA and chemotherapy. The study also will test whether MLA’s therapeutic effects are due to enhanced infiltration of immune cells, a result of blood-brain barrier disruption.
Principal Investigator: Rob Mitra, PhD, genetics Description: Dr. Mitra will use his CDI funding to study glioblastoma, the most devastating form of brain cancer. A School of Medicine colleague and co-investigator on this study, Joshua Rubin, MD, PhD, pediatrics, recently published studies exploring the observation that females are less likely than males to develop the disease, and when they do, they have better outcomes. He showed that these differences are due to distinct sex-specific cellular responses to chemotherapy drugs and to mutations affecting tumor suppressor genes. Recently, cellular identity has been tightly linked to differences in the activity of super enhancers, DNA regions that regulate the activity of genes in each cell. Dr. Mitra’s study will examine whether differences in super enhancer activity underlie male-versus-female cellular identity and contribute to the sex differences in rates of glioblastoma malignant transformation and treatment responses.
Principal Investigator: Qin Yang, MD, PhD, radiation oncology; and Dennis Hallahan, MD, radiation oncology Description: Reprogramming pediatric brain tumor cells into normal neurons is the ultimate goal of this innovative grant. In mice, protein inhibitors, called kinases, are able to reprogram brain tumor cells so that they lose their tumor-generating potential. Using cell culture studies, the researchers will try to reprogram human pediatric glioblastoma cells into neurons by combining kinases with small molecules known to prevent cellular resistance to reprogramming. This is the first step toward the development of novel reprogramming treatment strategies that, if successful, will extend the lives of, and potentially cure, children with brain tumors. Click here to learn more.
Principal Investigator: Suman Mondal, PhD, radiology, will use his CDI post-doctoral fellowship under the mentorship of Samuel Achilefu, PhD Description: Develop a prototype of a wearable goggle system that enables advanced fluorescence-guided surgery. Bioengineers at the School of Medicine devised a way to select the fluorescent molecule that best identifies different types of tumor cells. That key innovation of the new goggle system will enable more precise and effective surgery, thereby increasing survival rates and decreasing the need to treat residual tumors with chemotherapy and radiation. Click here to learn more.
Principal Investigator: Joshua Rubin, MD, PhD, pediatrics, and Bradley Schlaggar, MD, PhD, pediatrics and neurology Description: Discover ways to avoid creating cognitive deficits while treating children with brain tumors. Cutting-edge neuroimaging and advanced computational analysis will help the researchers more precisely pinpoint and validate biomarkers for cognitive deficits. This will lay the ground work for more sensitive and truly personalized metrics for improving cognitive outcomes for the ever-growing population of pediatric brain tumor survivors.
Project: Treating Acute Myeloid Leukemia (AML) Relapse in Pediatric or Young Adult (YA) Patients with Personalized Cellular Immunotherapy
|Principal Investigators: Fehniger, Bednarski, Romee Description: Acute myeloid leukemia (AML) in pediatric or young adult (YA) patients remains a clinical challenge. Most patients require a bone marrow transplant (BMT) for cure. For patients who relapse after BMT, survival is poor and new treatment approaches are desperately needed. Recent studies have shown that combined cytokine activation of white blood cells called natural killer (NK) cells improves their ability to combat myeloid leukemia. This project utilizes these cytokine-induced, memory-like NK cells as a personalized cellular immunotherapy strategy for relapsed pediatric/YA AML patients. Following chemotherapy treatment, patients are infused with a combination of their donor’s T cells and memory-like NK cells. This approach allows the T and memory-like NK cells to work together to eliminate the AML cells. Specific Aims: |
Principal Investigators: Gauvain, Dunn Description: Recurring pediatric brain tumors are associated with a very poor outcome. There is no cure for patients with relapsed cancerous brain tumors, and most children will not live more than two to three years. For many patients with recurrent brain tumors, there are few to no treatment options available. Thus, new treatments are desperately needed. Washington University School of Medicine is emerging as a world leader in developing personalized vaccines to fight against cancers. This project proposes the first-ever clinical trial to treat pediatric patients with relapsed or recurrent brain tumors with a personalized vaccine, referred to as a peptide vaccine, developed by targeting genetic abnormalities in each individual tumor. Specific Aims:
- Determine how safe, tolerable, and feasible it is to treat pediatric patients with recurrent brain tumors with a personalized peptide vaccine.
- Characterize how well the vaccine works by studying the immune system response in patients.
Principal Investigators: Liu, Chen Description: Diffuse intrinsic pontine glioma (DIPG) is the single greatest cause of brain tumor-related deaths in children. The location and diffuse nature of the disease prohibit surgical interventions; radiation therapy has proven inadequate for cure; and conventional chemotherapy is ineffective because drug delivery is limited by the intact blood-brain barrier (BBB). This project proposes to develop an innovative strategy for the improved treatment of DIPG using focused ultrasound (FUS)-enabled delivery of dissolvable, 64Cu-doped, chemotherapy-loaded copper nanoclusters (64Cu-CuNCs). Specific Aims:
- Optimize the synthesis 64Cu-CuNCs and FUS disruption of the BBB to maximize the delivery of 64Cu-CuNCs to the brain.
- Quantify drug accumulation using FUS-enabled delivery of 64Cu-CuNCs in a murine DIPG model.
- Measure the therapeutic efficacy and safety of 64Cu-CuNCs delivered by FUS in the DIPG model and develop an image-guided drug delivery strategy.
Principal Investigator: Albert Kim, M.D., Ph.D. Description: The brain cancer glioblastoma remains a devastating disease despite multidisciplinary treatments, with a median survival of only 15 months. To development novel therapies for this lethal disease, our goal is to identify the molecular pathways that control a clinically important and dynamic subpopulation of cancer cells called glioblastoma stem-like cells (GSCs) (also, cancer stem cells), which are resistant to conventional therapies and are responsible for cancer recurrence. An improved understanding of the molecular mechanisms governing the GSC state is therefore required to develop effective therapies against glioblastoma. Using a unique resource of patient tumor-derived GSCs, we propose to examine the role and detailed molecular mechanisms of an important protein complex called CDC20-Anaphase-Promoting Complex (CDC20-APC) in 1) the control of GSC identity and function and 2) therapeutic resistance of GSCs to standard treatments. Our long-term goal is to harness CDC20-APC-directed strategies to combat glioblastoma.
Principal Investigator: Kian Lim, M.D., Ph.D. Description: The prognosis of pancreatic cancer remains dismal and has not improved in the last 40 years. Therapeutic breakthrough must therefore come from novel discoveries in the biology of pancreatic cancer. We now found, for the first time in literature, that pancreatic cancer cells “armored” themselves by activating the innate immunity, a self-defense mechanism that is usually summoned when cells are injured or invaded by microorganisms. In doing so pancreatic cancer cells become highly aggressive and resistant to chemotherapeutics. Our approach is to “deactivate” such defense mechanisms in pancreatic cancer cells by inhibiting Interleukin-1 Receptor-Associated Kinase 4 (IRAK4), the master switch that controls the innate immune pathway. By doing so we found that pancreatic cancer cells become greatly weakened and are much more vulnerable to chemotherapy. In this proposal we will further investigate how pancreatic cancer cells summon their innate immune system, and develop new therapeutic strategies that can be tested in the clinic to improve patient outcome.
Principal Investigator: Ryan Teague, Ph.D., St. Louis University Description: Engaging a patient’s own immune system to fight cancer is the goal of checkpoint blockade immunotherapy. This strategy employs specific antibodies to block inhibitory receptors on tumor-reactive T cells, releasing the natural brakes of the immune system. While dramatic results have been observed, not all patients benefit from this treatment. Bringing the promise this immunotherapy to a broader range of patients requires a deeper understanding of the T cell responses elicited during treatment. Intense investigation has recently been focused on the diversity of those T cells that infiltrate tumors, and how the breadth of this T cell repertoire impacts patient outcomes. We hypothesize that checkpoint blockade immunotherapy elicits an enriched population of tumor-reactive T cells that otherwise would not contribute to cancer immunity. We predict that these newly engaged T cells positively influence the response to immunotherapy, and may be harnessed for improved outcomes for patients with cancer.
Principal Investigator: Jeff Milbrandt, M.D., Ph.D. Description: Incredible advances in cancer treatment have led to dramatic growth in the number of people with a history of cancer, increasing from ~3 million in 1971 to more than 13 million in 2014. As cancer treatments improve, a major challenge is to ensure that cancer survivors have the highest possible quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is a very common and often dose-limiting side effect of anti-cancer therapy. CIPN involves damage to nerves leading to numbness, tingling, and often, pain. These symptoms can persist for years after cessation of treatment, and so CIPN can significantly diminish patient’s quality-of-life both during and after treatment. Moreover, the development of CIPN often necessitates reducing drug dosage or switching chemotherapy regimens, and therefore limits the effectiveness of anti-cancer therapy. Currently, there are no effective treatments for CIPN. Many commonly used chemotherapeutics damage nerves and cause CIPN. Nerve damage can trigger a self-destruction program that leads to degeneration of axons, which are communication cables that transmitter information among nerve cells. In recent years we have made great progress in understanding the mechanism of this axon degeneration program. Here we test the idea that inhibiting such axon degeneration will slow or block the development of CIPN. If successful, these studies will identify new therapeutic targets for the prevention of chemotherapy-induced peripheral neuropathy and support our ultimate goal of enhancing the efficacy of anti-cancer therapies while improving the quality of life for cancer survivors.
Principal Investigator: Greg Longmore, PhD Description: Cancer patients die from the spread, or metastasis, of their cancer to other organs and when this occurs there is a general lack of effective treatment options. Thus, there is a critical need to better understand the metastatic process so as to develop new effective yet selective ways to prevent and treat the spread of breast cancer. It is now appreciated that the physical, cellular, and chemical microenvironment within and around the primary tumor site and metastatic sites influence the spread of tumor cells. In cancers these tumor microenvironmental (TME) factors differ from their normal tissue counterparts in composition, architecture, and function. Given, the importance of the TME in the metastatic process and that changes in the TME rarely involve acquired genetic mutations, we propose to develop a program project that is focused on elucidating the mechanisms by which the TME acts as an instigator or facilitator of metastasis.
Principal Investigator: Joseph Ippolito, M.D., Ph.D. Description: Glioblastoma Multiforme (GBM) is an extraordinarily aggressive cancer that comprises over half of all brain tumors. The overall prognosis is extremely poor with an average survival of 6 to 12 months following diagnosis. Interestingly, men with GBM do significantly worse than women with respect to more aggressive disease, shorter survival, and enhanced resistance to conventional therapy. The reason for this “sexual dimorphism” in GBM aggressiveness is currently unclear. We have preliminary evidence showing that male GBM’s have different metabolism than female GBM’s. Specifically, male cancer cells in a tumor may be better primed to supply each other with specific nutrients to survive. This phenomenon is referred to as “metabolic symbiosis” where lactic acid produced by glucose-consuming cancer cells in a tumor is metabolized by neighboring lactate-consuming cancer cells into energy that can sustain cell survival and is associated with therapeutic resistance. We are characterizing this process on the molecular level in GBM tumors and using this information to validate a novel PET tracer, 3-[11C] lactate in tandem with the clinical oncologic imaging workhorse, [18F] fluorodeoxyglucose (FDG) to image metabolic symbiosis in tumors. If successful, this novel imaging technique may pave the way to a new model in oncology where men and women with cancer need to be imaged and treated differently. Because 3-[11C] lactate is already approved in humans for non-oncologic neuroimaging applications at Washington University, we anticipate that this will be a rapidly translatable imaging paradigm.
Principal Investigator: William Gillanders, M.D. Description: Breast cancer is now recognized as a heterogeneous disease that will require a combination of prevention, diagnosis and treatment approaches to decrease mortality. While there has been significant advances in treating ER+ and HER2+ disease, Siteman Cancer Center sees 1100 breast cancer patients per year and many will ultimately succumb to their disease. This Siteman Investment Program Pre-SPORE application brings together a multidisciplinary team of investigators leveraging institutional strengths in basic and translational research. The intent is to form a competitive NCI Breast Specialized Program of Research Excellence (SPORE) Program that will enable rapid clinical translation of novel basic science discoveries with the goal of impacting patient care. Siteman Investment Program funds will provide critical initial support for the development of a Breast Cancer SPORE at Siteman Cancer Center with a focus on tumor immunology, oncologic imaging, surgical oncology, and breast cancer biology.
Principal Investigator: Katherine Fuh, M.D., Ph.D. & Greg Longmore, M.D. Description: Cancer metastasis causes more deaths than primary tumors. It is difficult to prevent or treat metastasis with the current treatment options of surgery and chemotherapy. We have designed projects that have already identified genes responsible for metastasis in a clinically relevant manner. By identifying these genes, we are advancing medicine by knowing what to target in metastasis. By knowing what to target, we are able to develop selective therapies against these targets. We used this funding to perform two clinically relevant screens using patient tumors. The functional screen incorporated a common site for ovarian cancer metastasis, the omentum, which is the first step of metastasis. Over the past year, the assay was developed and we have begun screening tumor cells for molecules that are important for their attachment and invasion of the omentum. Importantly we have identified and confirmed a novel therapeutic target, and are developing new small molecule inhibitors of this target. We are now in a position to test these new inhibitors as to their efficacy in preventing ovarian metastasis in preclinical models.
Principal Investigator: William Gillanders, M.D. Description: The trial was officially opened in January of this year. Since then, 100 patients have been screened for eligibility. Five patients have been consented for the trial since January 2015. As part of the eligibility criteria, mammaglobin-A status is checked in the patient’s tumor by immunohistochemistry (IHC). Additionally, the Ki67 level is assessed after two weeks of neoadjuvant endocrine therapy by IHC. Two of the five patients were not eligible due to negative mammaglobin expression. One of the five patients was not eligible due to elevated BMI. One of the five patients received one dose of the mammaglobin-A vaccine by electroporation but withdrew consent afterwards due to bilateral arm pain that occurred after vaccination. Lastly, the most recently-recruited patient was not eligible due to elevated Ki67 after receiving neoadjuvant endocrine therapy. Partial HLA typing was initially performed by flow cytometry (HLA-A2, -A3, and -B7). However, we also implemented a complete HLA typing through DNA sequencing at the McDonnell Genome Institute at Washington University.
Principal Investigator: William Hawkins, M.D. Description: Pancreatic cancer is a devastating disease and current therapies have limited efficacy. Limitations of current therapeutic strategies include a highly immunosuppressive immune environment, lack of cancer-selective drug delivery, and inability to target KRAS driven proliferation. The ultimate goal of this Team Science Award is to improve the survival of patients with pancreatic ductal adenocarcinoma (PDAC). The immediate goal our Team Science Award is to advance the translational science in support of our recently submitted SPORE application. We received a highly competitive but not fundable score on our initial application. This Team Science Award was extremely helpful in the preparations for the resubmission. It allowed us to strengthen our application for resubmission and address the majority of the reviewers concerns. New preliminary data was used to strengthen our SPORE application. The CFF continues to help us acquire translational data on our basic science discoveries. Building on our desire to further develop these collaborative patient-oriented projects, we propose to continue advancing these collaborative patient-oriented projects with the goal of developing new therapeutic approaches for PDAC.
Project: MRI-guided Laser Heat Ablation to Induce Blood Brain Barrier Breakdown in Pediatric Brain Tumors
Principal Investigator: Karen Gauvain, M.D., MSPH & David Limbrick, M.D., Ph.D. Description: Magnetic resonance imaging (MRI)-guided laser ablation (MLA) is a minimally invasive laser surgery designed for the treatment of surgically inoperable brain tumors. One challenge to treating brain tumors is the blood-brain barrier (BBB), which separates circulating blood from the fluid of the nervous system, preventing chemotherapy drugs from penetrating the brain. In adults, MLA disrupts the BBB, allowing for better penetration of chemotherapy drugs into the tumor. The purpose of this study is to examine the outcomes of pediatric patients with newly diagnosed and recurrent brain tumors who are treated with MLA and chemotherapy. The study will also test whether MLA’s therapeutic effects are due to enhanced infiltration of immune cells into brain tumors as a result of BBB disruption. Specific Aims:
- Use serum biomarkers and advanced MRI techniques to identify the time window of maximal BBB disruption after MLA for optimal chemotherapeutic effects in children.
- Determine the progression-free survival and overall survival of children undergoing MLA plus chemotherapy versus standard chemotherapy alone.
- Determine whether the anti-tumor immune response is enhanced following MLA.
Principal Investigator: Robi Mitra, Ph.D. Description: Glioblastoma is the most devastating form of brain cancer, and most glioblastoma tumors are resistant to conventional therapies. Females are less likely than males to develop the disease, and when they do, they have better outcomes. Previous work showed that these differences are due to cellular identity, specifically, distinct sex-specific cellular responses to chemotherapeutics and to mutations affecting tumor suppressor genes. Recently, cellular identity has been tightly linked to differences in the activity of super enhancers, roughly 300 regions in DNA that regulate the activity of genes in each cell. This project will examine whether differences in super enhancer activity underlie male-versus-female cellular identity and contribute to the sex differences in thresholds for transformation (i.e., cancer rates) and outcomes (i.e., drug sensitivity). Specific Aims:
- Enumerate sex differences in super enhancer activity and determine the effects on gene expression.
- Identify genes that contribute to sex differences in thresholds for malignant transformation.
- Map the gene regulatory network underlying sex differences in thresholds for transformation.
Project: A Phase-I Trial of Familial Haploidentical Nonmyeloablative Bone Marrow Transplantation in Children
Principal Investigator: Shalini Shenoy, M.D. Description: Sickle cell disease (SCD) is a genetic disorder that distorts red cells, inhibits blood supply, and damages the brain, lungs, kidneys and muscles. The disease affects more than 100,000 individuals in the United States, causing stroke and poor quality of life in childhood and mortality in young adulthood. Hematopoietic cell transplantation (HCT)-a procedure involving the infusion of bone marrow stem cells that give rise to healthy blood cells-has been shown to cure SCD when using a fully tissue-matched healthy donor, although there is a <35% chance of a fully matched donor being available. In addition, HCT causes side effects such as infections, sterility, and graft-versus-host disease (GVHD). This proposal is a pilot trial to test a new approach that may improve hematopoietic cell transplantation outcomes in SCD, using parents as haploidentical donors and additional therapies to manage GVGD. Specific Aims:
- Evaluate overall and disease-free survival after novel haploidentical (half-matched) HCT therapy in SCD children.
- Evaluate HCT-specific outcomes, including graft vs host disease and immune recovery.
- Evaluate SCD-related organ function after HCT.
Principal Investigator: Suman Mondal, Ph.D. Description: The extent of surgical resection is the most important factor for determining survival in pediatric brain tumors. Surgical outcomes may be improved through fluorescence-guided surgery (FGS). A clinically approved FGS procedure that uses fluorescence from a molecule called protoporphyrin IX (PpIX) can highlight high-grade pediatric tumors, but this approach requires expensive, bulky surgical microscopes and may not identify low-grade tumors, which account for 30-50% of all pediatric brain tumors. By contrast, the highly cancer-specific near-infrared fluorescent probe LS301 can potentially highlight low-grade tumors, while the wearable goggle augmented imaging and navigation system (GAINS) allows inexpensive real-time intraoperative FGS. The goal of this study is to develop a dual PpIX-LS301-compatible wearable goggle prototype that will enable sensitive detection of low-grade pediatric tumors and eventual clinical translation. Specific Aims:
- Development of a dual PpIX-LS301-compatible GAINS (goggle) prototype.
- In vitro prototype characterization to assess sensitivity, resolution, and ease of usage in tissue-like material.
- Evaluation of tumor resection in mouse models of low- and high-grade pediatric brain tumors.
Principal Investigator: Katherine Fuh, M.D. Description: 65% of women diagnosed with ovarian cancer will die of this disease. Metastatic ovarian cancer remains an incurable cancer and novel treatments are urgently needed. By identifying new gene expression of cancers that have metastasized in the context of how cancers communicate to the supporting tumor microenvironment, we have a unique opportunity to find biologically relevant genes. We are using cells from the tumor microenvironment that pancreatic, colorectal and prostate cancers use to invade and metastasize. Researchers will be able to use the same technique and find genes that can be translated to other cancers. The discoveries made in these projects will pave the way for development of additional agents that will not only treat the cancer but also lead to less toxicity than chemotherapy. This could help change the treatment of ovarian cancer which has used the same chemotherapy agents for 20 years.
Principal Investigator: William Hawkins, M.D. Description: Pancreatic cancer is a devastating disease and current therapies have limited efficacy. Limitations of current therapeutic strategies include a highly immunosuppressive immune environment, lack of cancer-selective drug delivery, and inability to target KRAS driven proliferation. The ultimate goal of this Team Science Award is to improve the survival of patients with pancreatic ductal adenocarcinoma (PDAC). The immediate goal is to obtain additional preliminary data in support of a pending PDAC SPORE application. Our near-term goal is to advance four new and potentially transformative therapeutic approaches into the clinic for evaluation. We propose to key proof-of-concept preliminary studies that will provide strong support for the four collaborative patient-oriented projects developing new therapeutic approaches for PDAC.
Principal Investigator: Farrokh Dehdashti, M.D. Description: The majority of patients with breast cancer are tested for presence of receptors in their tumor tissue from biopsy to see if their disease is sensitive to different hormones such as estrogen and progesterone. Once tested, they are classified as being estrogen-receptor positive (ER+), progesterone-receptor positive (PgR+), or both. Prior research has shown that patients with hormone positive disease usually have slower growing tumors and respond well to endocrine therapies (ET), which is considered a less toxic form of treatment when compared to chemotherapy. There is no test to separate patients with ER+ breast cancer who respond to ET from patients with ER+ breast cancer who do not respond to ET. A test which is non-invasive and able to characterize (whether tumor has receptors and whether the receptors are functional) the entire tumor in a single image is needed. Such a test would aid doctors in determining the best possible treatment for breast cancer patients. Positive results from this project could ultimately lead to individualized treatment to prevent unnecessary treatment for patients in the near future.
Principal Investigator: Jonathan McConathy, M.D., Ph.D. Description: The clinical outcome of patients with brain tumors is variable; some patients survive for many years while others succumb rapidly to the disease. Surgery is an important treatment for brain tumors. Complete or near-complete removal of brain tumors increases the chances of survival. We propose to combine MRI with metabolic imaging to better define tumor borders prior to surgery. If effective, our goal is to make FDOPA-PET/MRI routinely available to our brain tumor patients and to the physicians caring for them in order to improve surgical outcomes and identify patients with aggressive brain tumors needing urgent therapy.
Principal Investigator: John DiPersio, M.D., Ph.D. Description: In this application we will continue to develop and test in humans for the first time novel immune-based therapies and cellular therapies for the treatment of acute myelogenous leukemia (AML). Approximately 60-80% of patients with AML with either relapse or have disease that is refractory to initial chemotherapy. We will generate and test in the laboratory and in first-in-human clinical trials novel retargeting agents (small proteins), and will modify and optimize these agents so that natural killer (NK) and cytotoxic T lymphocyte effector cells more effectively kill the AML cancer cells. We will also test a new class of NK cells for their ability to kill AML cells. Finally, we will attempt to identify novel proteins on the surface of AML cells for the future development of targeting agents that engage either T cells, NK cells or other immune effector cells. We believe these new therapeutic approaches will be profoundly effective in AML and pave the way for development of similar reagents and approaches for the treatment of other malignancies.
Principal Investigator: Jason C. Mills, MD, PhD Co-Investigators: Nicholas Davidson, MD; Blair Madison, PhD, Deborah Rubin, MD Goal: Identify which genes trigger pre-cancerous growths in the stomach and intestines and find drugs targeting those genes to stop cancer before it starts. Description: Cancers of the colon, rectum and stomach are among the most common and deadliest in the world. Because these cancers first show pre-cancerous changes, such as intestinal polyps, preventing these cancers or even reversing them may be possible if researchers understood how they begin. This research will study genes and cell-to-cell interactions that foster pre-cancerous growths in the stomach and intestines. The goal is to identify which genes are required for growth of precancerous lesions and determine how individual patients’ genes interacts with potential therapeutic drugs.
Principal Investigator: Dale Dorsett, PhD Co-Investigators: Alessandro Vindigni, PhD; Susana Gonzalo, PhD Goal: Discover how cells repair, replicate and pass on their genomes after damage caused by chemotherapy, in order to improve cancer therapy effectiveness and decrease chemotherapy side effects. Description: Chemotherapy affects both cancerous and non-cancerous cells, while causing DNA mutations that can spur new tumor growth. This research will define the roles of certain genes in DNA replication and repair, learn how they are altered in cancer cells and in treatment with chemotherapy that damages DNA. Insights gained promise to improve chemotherapy’s effectiveness against cancer cells as well as drugs’ selectivity to protect normal cells.
Principal Investigator: Todd A. Fehniger, MD, PhD Co-Investigators: Megan Cooper, MD, PhD; Jackie Payton, MD, PhD; Tim Ley, MD; Steve Oh, MD, PhD Goal: Advance understanding of how natural killer (NK) cells work in order to harness their power to develop immunotherapy-based cancer treatment. Description: Natural killer (NK) cells are immune cells that recognize and help to eliminate cancers, especially blood cancers. This research seeks to understand the mechanisms behind a new finding in NK cell biology, termed innate memory, that generates NK cells that are better equipped to eliminate cancer. Ultimately, this research will help to advance NK cell immunotherapy, and lead to the next generation of clinical trials using memory-like NK cells for cancer treatment.
Principal Investigator: David G. DeNardo, PhD Co-Investigator: Andrea Wang-Gilliam, MD, PhD Goal: Develop a more effective way to treat pancreatic cancer by decreasing the ability of cancer cells to build a protective barrier around tumors, and then targeting the cancer with immunotherapy. Description: Pancreatic cancer has a dismal survival rate because it generally metastasizes early and existing chemotherapy isn’t very effective for this type of cancer. Pancreatic cancer has a unique tumor microenvironment that creates a protective, scar-tissue-like barrier so therapies can’t get through to the cancerous cells. This research would target the mechanisms that create these barriers to decrease pancreatic cell growth, while allowing effective immunotherapy to reach and destroy the remaining tumor cells.
Principal Investigator: Todd Druley, M.D., Ph.D. Description: Acute myeloid leukemia (AML) is a challenging malignancy to treat in pediatric patients. Disease monitoring following treatment involves quantifying small numbers of leukemic cells that remain in the patient using minimal residual disease (MRD) assays. Roughly one-third of AML cases do not harbor markers amenable to the gold-standard methods for assessing MRD and predicting relapse risk in AML. Sequencing studies have demonstrated that virtually all AML cases contain leukemia-specific single-nucleotide mutations. Error-corrected next-generation sequencing (ECS), employed by the Druley lab, enables the detection of rare leukemic cells harboring these mutations. This project will enable ECS targeting dozens of genes to assess MRD in nearly all pediatric AML cases with comparable accuracy to conventional methods, leading to improved genetic diagnostics for pediatric cancer patients. The aims of this proposal are to: Extend ECS to test multiple different recurrently mutated genes in AML. Apply ECS-MRD testing to approximately 150 remission pediatric AML samples with MRD status and correlate MRD status with outcome. Validate the criteria established in Aim 2 using approximately 100 pediatric AML remission samples with diagnostic genome sequencing and MRD status. This new assay will extend the life-saving capability of MRD to virtually every pediatric AML patient.
Principal Investigator: Nima Mosammaparast, M.D., Ph.D. Description: Pediatric glioblastoma is an aggressive brain tumor associated with a very poor prognosis. Commonly used chemotherapeutic drugs for adult glioblastoma are typically not effective in the pediatric population. The proposed research is aimed at understanding a newly discovered protein complex that regulates molecular pathways critical for glioblastoma chemotherapy. It is possible that this enzyme complex, called OTUD4, could be inhibited to improve the response of pediatric glioblastoma to chemotherapy. The proposal aims to expand significant preliminary data on the OTUD4 pathway to determine whether this pathway could be targeted in pediatric glioblastomas. The aims of this proposal are: To determine whether inhibition of a deubiquitinase complex consisting of OTUD4 and USP7/9X promotes sensitivity to chemotherapy-induced alkylation damage in pediatric glioblastomas, using a preclinical model. Understanding how tumor cells regulate the proteins responsible for repairing damage induced by chemotherapy will have broad implications for not only pediatric glioblastoma, but numerous other tumors that are treated with these drugs.
Principal Investigator: Joshua Rubin, M.D., Ph.D.; Albert Kim, M.D.,Ph.D.; Kristen Kroll, Ph.D.; and Hiroko Yano, Ph.D. Description: Despite decades of research on malignant brain tumors in children, an understanding of the fundamental mechanisms of tumorigenesis and the requirements for effective treatment remains inadequate. This proposal addresses the hypothesis that malignant brain tumors in children are caused by abnormalities in chromatin- a complex of DNA and proteins that forms chromosomes. Recent research has shown that mutations in chromatin regulatory proteins or in histone H3-a protein found in chromatin-are common to malignant brain tumors in children. Understanding how the chromatin state (also known as “epigenetics”) regulates tumor genesis and how it might dictate the therapeutic response is the focus of this proposal. The aims of this proposal are to test whether: A specific pattern of a chromatin modification called histone H3 lysine 27 tri-methylation (H3K27me3) is associated with a chromatin signature and gene-expression program characteristic of undifferentiated, therapy-resistant, tumor-initiating cells. Loss of this H3K27me3 pattern induces a chromatin state characteristic of more differentiated, non-clonogenic, and therapeutically vulnerable cells. By testing whether the balance between H3K27 histone methyltransferase and demethylase activities can determine malignant transformation and the therapeutic response, these studies could shed light on the mechanisms of brain tumorigenesis and lead to the development of novel therapeutics targeting brain tumor epigenetics and histone dysregulation.
Principal Investigator: Gerald Linette, MD, PhD; Co-investigator: Beatriz Carreno, PhD; Elaine Mardis, PhD Summary: Goal is to create a personalized vaccine to activate the immune system to fight melanoma. Description: The incidence of malignant melanoma (skin cancer) continues to rise worldwide. Metastatic melanoma remains an incurable cancer and novel treatments are urgently needed. The good news is recent advances with immunotherapy-which triggers the body’s own immune system to fight cancer-suggest that lasting remissions are possible. Mutations, or alterations in the DNA, due to sunlight exposure accumulate over time and promote the transformation of benign pigmented moles to malignant melanoma. Dr. Linette’s research team believes that the immune system has the ability to recognize the sunlight-induced cell alterations as foreign and mount an immune response to attack the melanoma. The research project will analyze the melanoma genomes of five patients and identify mutations that are unique to each individual. Using these specific mutations, researchers will develop a customized cellular therapy vaccine to treat patients with advanced melanoma.
Principal Investigator: John F. DiPersio, MD, PhD; Co-investigators: Jaebok Choi, PhD; Mark Schroeder, MD Summary: Goal is to determine if a drug, given just after bone marrow transplant, can potentially reduce a painful, life-threatening side effect. Description: Cancers affecting the blood, bone marrow and lymph nodes-such as leukemia-remain a significant public health problem, accounting for about 10 percent of new cancer diagnoses. The good news is patients with these types of cancers can often be cured by bone marrow transplants. One type of cell in the donated transplant is a white blood cell (lymphocyte) called a T cell. As part of the immune system, T cells are the primary leukemia-fighting cells. However, in about 40 percent of cases, the donated T cells sometimes become overzealous and also attack the patient’s skin, intestines, liver, and mucosa. This very painful and sometimes fatal condition is known as Graft versus Host Disease (GvHD). It affects nearly 50 percent of patients who have had a bone marrow transplant. In Dr. DiPersio’s study, he and his team are exploring whether acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) patients who receive bone marrow transplants experience less GvHD when given azacytidine, a drug already approved by the FDA for other purposes. In previous studies, the drug was shown to alter T cells so they retained their ability to attack the leukemia cells, but substantially reduced their undesired GvHD effect-sometimes totally eliminating it. This could be a significant step forward in cancer care. The hope is that this simple approach will reduce rates of GvHD after transplant and improve survival and quality of life after transplant.
Principal Investigator: Lee Ratner, MD, PhD Summary: Goal is to determine if a certain class of drugs is effective in treating Kaposi’s Sarcoma and possibly other cancers. Description: Dr. Ratner is launching a unique clinical study of AIDS-associated Kaposi’s Sarcoma (KS). KS is an incurable tumor that often involves the skin, lungs, and gastrointestinal tract of patients with AIDS (acquired immunodeficiency syndrome) or other immunosuppressed conditions. KS is also found in elderly men in the Mediterranean area and boys in central Africa. The tumor is caused by the KS herpes virus (KSHV). The Notch pathway is important for stem cells, development and new blood vessel formation. Mutations in Notch regulators appear frequently in a wide range of cancers; the Notch pathway can feed cancer growth. Drugs, known as gamma secretase inhibitors (GSI), have been developed to block Notch. In tissue culture studies, GSIs cause KS cell death. Dr. Ratner’s project is one of the first studies of any GSI to treat a specific form of cancer, i.e. KS. The next steps are for Dr. Ratner to work with patients to assess tolerance and response of KS to GSI; to determine whether levels of Notch regulators and Notch target genes are major determinants of how the cancer responds to the GSIs; and to determine which KSHV proteins are expressed in each patient’s tumor and whether a specific pattern of protein expression predicts how the cancer responds. In addition, the study will determine what role new blood vessel formation plays in how GSIs work. The outcome of this study could lead to new treatment for KS and could provide new information about the use of GSIs in other cancers.
Principal Investigator: William Gillanders, MD; Co-investigators: Timothy Fleming, PhD; Simon Goedegebuure, PhD; Feng Gao, MD, PhD; A. Craig Lockhart, MD; Foluso Ademuyiwa, MD; David Denardo, PhD Summary: Goal is to advance the development of a vaccine with the potential to prevent breast cancer. Description: Cancer vaccines have generated considerable enthusiasm because of their tremendous potential for cancer prevention. Dr. Gillanders and his team have identified mammaglobin-A, a breast cancer-associated protein, as an excellent target for vaccine therapy. Mammaglobin-A is expressed in almost all breast cancers, and can potently stimulate the immune system. Thus, a mammaglobin-A vaccine would have significant potential for breast cancer prevention. Through the study, Dr. Gillanders and his team will gain additional information about the vaccine’s safety, assess the vaccine’s ability to induce an immune response, and help optimize the vaccine’s effectiveness against breast cancer. This study will significantly advance the clinical development of this innovative mammaglobin-A DNA vaccine.
Principal Investigator: Ravindra Uppaluri, MD, PhD; Co-investigators: James Lewis Jr., MD; Michael Onken, PhD Summary: Goal is to develop a genetic test for individual oral cancer patients that helps doctors prevent overtreatment by tailoring aggressive therapy only for those who need it. Description: Oral cavity squamous cell carcinoma (OCSCC), a form of oral cancer, is a global health problem. More than 27,000 people are diagnosed each year in the United States alone. Unfortunately, early stage oral cancer is not always properly assessed, which can lead to overtreatment with surgery or radiation. Those treatments can lead to higher costs as well as more complications. When OCSCC patients are first seen, treating physicians must decide whether the cancer has spread from the mouth to neck lymph nodes. Cancer that has spread to lymph nodes has a poorer prognosis because it may mean cancer can recur after treatment or has spread throughout the body. However, even if there are no obvious signs that cancer is in the lymph nodes, some surgeons prophylactically remove most of the lymph nodes in the neck prophylactically anyway. Unfortunately, this is an unnecessary operation in 70 to 80 percent of these patients and is associated with extended hospital stays, financial burden and surgical complications, including weakness in the shoulder due to nerve damage. Dr. Uppaluri is studying the genetic signature of aggressive oral cancer tumors to predict which cancers are more likely to spread. If the study proves that the genetic predictor tests are as accurate as the pathology information provided by removing neck lymph nodes, then the test could be used to screen patients for metastatic disease without subjecting them to neck surgery. The data collected from this study will support the development of the genetic test to reduce unnecessary surgery and provide patients with important information about their prognosis, such as whether the tumor is aggressive or likely to spread.
Principal Investigator: John F. DiPersio, MD; Co-investigators: Daniel Link, MD; Todd Fehniger, MD, PhD; William Frazier, PhD; Geoffrey Uy, MD; Reid Townsend, PhD; Michael Rettig, PhD; Rizwan Romee, MD Summary: Goal is to find new avenues to treat leukemia by activating the patient’s own immune cells. Description: Through this study, Dr. DiPersio and his team will develop and test novel immune based therapies and cellular therapies to treat acute myelogenous leukemia (AML). About 60 to 80 percent of patients with AML will either relapse or have disease that doesn’t respond to initial chemotherapy. Unfortunately, novel chemotherapy drugs have not improved patient outcomes and no new agents have been approved for AML since 1990. Stem cell transplantation is one treatment approach to AML but it comes with some significant, treatment-related risks that can affect quality of life or even be life-threatening. Targeted immunotherapy represents a promising avenue for improving the outcomes of patients with AML. Dr. DiPersio’s team is tackling AML through a three-pronged approach. First, they will generate and test small proteins derived from antibodies that target unique antigens expressed or overexpressed on AML cells compared to normal cells. They will also modify and optimize these proteins so that natural killer (NK) and other cancer-fighting cells, in addition to T cells (the primary leukemia-fighting cells), more effectively kill the AML cancer cells. In another trial, the team will test a new class of NK cells for their ability to kill AML cells. Finally, they will attempt to identify antigens on AML cells for the future development of targeting agents that engage other immune cells to attack cancer cells. These novel therapeutic approaches show promise to be profoundly effective in AML, a disease for which therapy has not changed for more than 40 years. The discoveries made in these projects will pave the way for development of additional agents and approaches to treat other blood and solid tumor cancers.
Principal Investigator: A. Craig Lockhart, MD; Co-investigators: Jean Wang, MD, PhD; Jason Mills, MD, PhD; Yan Yan, MD, PhD Summary: Goal is to determine if a current hormonal therapy drug can prevent esophageal cancer. Description: Barrett’s esophagus (BE) is a condition in which the cells of the lower esophagus become damaged. This is usually caused by repeated exposure to stomach acid from acid reflux. Barrett’s esophagus has no current treatment and can lead to esophageal cancer. Dr. Lockhart’s research aims to prevent cancer from forming by treating patients with Barrett’s esophagus with tamoxifen, an established hormonal therapy, to determine whether the drug can reverse some of the molecular changes associated with this condition. Tamoxifen is already a well-studied drug with few side effects. If this treatment strategy proves successful, this could represent a new treatment approach for patients with Barrett’s esophagus-and even prevent esophageal cancer. In addition, repurposing an already approved cancer drug as a cancer preventative can shorten the time needed to bring a new therapy to use in patients.
Principal Investigator: Todd Druley, M.D., Ph.D. Description: Infant leukemia (IL) remains the deadliest of all pediatric leukemias, with a survival rate of less than 50%. Dr. Druley found that IL patients are born with a significant enrichment of rare and damaging genetic variants in leukemia-associated genes. Every infant with acute myeloid leukemia (AML) inherited damaging MLL3 gene variants from each parent, suggesting that, in a specific genomic context, infant AML requires dysfunction of MLL3. Potential Impact: The use of genomics as a discovery tool for IL could lead to new insights into how inherited genetic variation influences complex disease. Moreover, this research could enable testing of novel therapeutic agents and lead to new strategies for engineering blood stem cells that could be transplanted into IL patients, ultimately improving clinical outcomes.
Principal Investigator: Jeffrey Magee, M.D. Description: Leukemia is the most common pediatric cancer, and it is among the most common causes of disease-related death in children. We are interested in understanding how mutations in blood-forming stem cells cause leukemia. We have shown that a mutation that increases stem cell numbers and causes rapid leukemia development at one stage of life may be relatively benign at another. We are working to understand how and why certain mutations have age-dependent effects on stem cells and evolving leukemia cells. Potential Impact: Our overarching goal is to develop strategies to more precisely and effectively treat childhood leukemia.
Principal Investigator: Vikas Dharnidharka, M.D., Ph.D. Description: Post-transplant lymphoproliferative disorder (PTLD) is a malignant transformation of white blood cells called lymphocytes that occurs in solid-organ or tissue-transplant recipients, resulting in significant morbidity and mortality. Many PTLD cases are caused by the Epstein-Barr virus (EBV), but the remaining cases have no known cause. The goal is to study the underlying causes and predictors of clinical outcomes in EBV-positive and EBV-negative PTLD cases. Newly available next-generation deep shotgun sequencing technologies through the Washington University Genome Institute will be used to simultaneously detect many different known viral sequences from extracted stored PTLD tissue paraffin blocks. Potential Impact: This high-risk multidisciplinary project could have a major impact in the field, potentially revealing not only the causes of EBV-negative PTLD cases, but also genomic variants that could be studied for future therapeutic targets.
Principal Investigators: Dr. Rebecca Aft and Dr. Mark Watson Description: Metastasis is the most significant contributor to mortality in breast cancer patients. Data suggests that only a small subset of cells within the primary tumor possess metastatic potential. Dr. Aft hopes to develop a molecular “signature” for this subset of cells that will reveal their presence, gauge their metastatic potential, and provide guidance on systemic therapy. Her findings lead to the development of a standardized test to guide targeted therapy directed against micro-metastatic disease. The successful completion of this study would significantly alter the therapeutic management of breast cancer patients based on the presence, classification, and variations in metastasizing tumor cells.
Principal Investigator: Dr. John DiPersio Description: In an attempt to ward off relapse of certain diseases, such as leukemia, some patients receive a bone marrow transplant. While this approach can be curative, 50% of all bone marrow transplant patients eventually develop Graft vs. Host Disease (GvHD), a life threatening complication. In GvHD, the donor T-cells attack not only the patient’s cancer cells but other healthy cells as well. Although stem cell transplantation represents the best and most effective approach to cure patients with leukemia, pre-leukemia, lymphoma and other conditions adversely affecting bone marrow function, it is also the most risky. The “holy grail” for stem cell transplantation researchers is to eliminate GvHD while maintaining a potent graft vs. cancer effect. Building on previous findings, Dr. DiPersio will conduct a clinical trial to determine if azacitidine, administered shortly after transplant, can suppress or eliminate GvHD without impairing the curative potential of the transplanted T-cells. This study may offer opportunities to reduce life-threatening toxicities of stem cell transplantation; and to permit use of mismatched donors, thus opening up this potentially curative treatment to all patients.
Principal Investigator: Dr. Gerry Linette Description: Despite recent treatment advances, metastatic melanoma remains an incurable malignancy with an expected survival of 12 to 14 months. Investigational cancer vaccines as well as adoptive T cell therapies are now beginning to show efficacy in early phase clinical trials. However, a critical barrier facing investigators developing these cellular therapies is the limited number of validated melanoma (tumor) antigens that can be use to activate a patient’s T cell immune system. By coupling gene sequencing with laboratory testing, Dr. Linette and collaborators at the Genome Institute plan to develop genomics-guided tumor antigen identification for incorporation in vaccines that are unique to each patient’s tumor. This study may delineate a “road-map” for development of personalized cellular therapies for the treatment of advanced melanoma.
Principal Investigators: Drs. David Linehan, David Denardo, Andrea Wang-Gillam, Jason Weber, William Hawkins, and Dirk Spitzer Description: Pancreatic cancer is highly resistant to chemotherapy; consequently, patient survival rates are extremely low, less than 3%. With 2011 Cancer Frontier Fund support, team members worked to determine why pancreatic cancer is so resistant to chemotherapy. The initial investigations yielded significant findings, which led to a clinical trial and a second year of funding from the Cancer Frontier Fund to continue this promising line of research. Researchers identified new therapeutic targets and disease biomarkers linked to patient survival as well as treatment resistance. By understanding how cancer cells evade chemotherapy, researchers can develop more effective strategies to overcome this resistance and improve patient outcomes.
Principal Investigators: Dr. Ryan C. Fields, Dr. Peter Goedegebuure, Dr. A. Craig Lockhart, Dr. Christopher Maher Elaine Mardis, and Dr. Richard K. Wilson Description: Little is known about the biology in the genetic progression from primary tumor to metastatic disease (mCRC) in colorectal cancer. To address the unmet clinical need of better treatments for colorectal cancer that has spread, this study will conduct an advanced genetic and epigenetic analysis of matched tissue samples (i.e. from the same patient) from primary and mCRC tumor specimens in hopes of identifying novel therapeutic targets. This “team science” effort consists of four overlapping projects that investigate specific aspects of metastatic tumor biology to gain a clearer understanding of the pathways by which primary tumors gain the ability to metastasize. This project represents a unique and incredible opportunity in the field of genomics for colorectal cancer and will lay the foundation for future and continued multidisciplinary applications.
Using Heat Ablation to Disrupt the Blood Brain Barrier to Enhance Delivery of Chemotherapy in the Treatment of Recurrent Glioblastoma
Principal Investigators: Dr. David Tran, Dr. Eric Leuthardt, and Dr. Joshua Shimony Description: Glioblastoma multiforme (GBM) is the deadliest high-grade malignant brain tumor in adults. Combined radiation and chemotherapy produces only a small survival benefit, with most patients dying within five years. One challenge to treatment is the inability of available drugs to pass the blood-brain barrier, a mechanism that protects the central nervous system by creating a barrier between brain tissues and circulating blood. This study will investigate whether laser heat ablation guided by brain MRI is effective in temporarily disrupting the blood-brain barrier, thereby facilitating penetration of drugs into the tumor and the surrounding area, and improving patient response to treatment. If proven effective, this approach will increase the number of drugs that could be used for successful treatment of GBM and could also be applied to treatments of other primary brain tumors and brain metastases.
Principal Investigator: Dr. Grant Challen Description: Acute lymphoblastic leukemia (ALL) is the most common cancer in children. A subgroup with T-cell ALL (T-ALL) have a poor prognosis. DNA methylation is an “epigenetic” modification that does not alter the DNA sequence, but produces marks or “flags” on DNA that can turn genes on or off. Cancer cells exhibit an altered pattern of these methylation flags. As mutations in DNMT3A, an enzyme that establishes methylation flags, have been discovered in T-ALL patients, we propose that DNMT3A mutations predispose T-cells to become cancerous. We have shown that mice lacking Dnmt3a are more susceptible to T-ALL development. Moreover, immature T-cells in the thymus of mice lacking Dnmt3a have an overactive pathway called Notch. These studies will investigate the links between Dnmt3a-mediated DNA methylation, Notch, and ALL. The long-term goal of this project is to help develop treatments and improve the outcomes for patients with acute lymphoblastic leukemia, the most common cancer in children.
Principal Investigators: Dr. Jason Weber, Dr. Jeffrey Leonard Description: Gliomas are one of the most common brain tumors in children. The survival rate for patients with a high-grade form of these tumors is less than one year. This project will investigate the role of two proteins located in the brain – nucleolin (NCL) and nucleophosmin (NPM) – in the development of gliomas. That will help establish whether to target these proteins in treating these tumors. Potential impact of the project: We will identify whether NCL, NPM and their interactions are important for glioma tumor cell growth and survival, and could be potential anti-cancer targets for treating pediatric gliomas.
Principal Investigators: David C. Linehan, MD; Davide DeNardo, PhD Description: Almost all patients that develop pancreatic cancer require chemotherapy, yet it is highly resistant to treatment and has a median survival of only 4-6 months. This project will study biologic mechanisms behind this resistance and devise novel strategies to overcome this. Three distinct hypotheses will be pursued, each probing a mechanism of therapeutic resistance and a novel therapeutic approach. All these aspects will be combined to understand how the various mechanisms are integrated. This will also guide the development of strategies to improve the response to treatment, and help identify patients likely to benefit from the therapies.
Principal Investigator: Cynthia Ma, MD Description: In patients with HER2 positive breast cancer, anti-HER2 drugs, including trastuzumab (Herceptin) and lapatinib (Tykerb), are readily available and used with good results. However, these drugs are not FDA-approved for HER2 negative breast cancer. This project seeks to establish that this subset of HER2 negative patients can be effectively treated with anti-HER2 agents. If successful, the results will lead to larger trials and, some day, treatment access for all patients with this cancer to the increasing numbers of anti-HER2 medications.
Principal Investigator: Jeremiah Morrissey, PhD Description: When diagnosed by symptoms, patients with the two predominant forms of kidney cancer (clear cell and papillary) have poor outcomes. When caught earlier, patient survival rates exceed 70%. There is currently no method of screening for kidney cancer and tumors are usually discovered due to other medical investigations. The team will screen large groups of patients to determine if certain biomarkers can correctly identify and predict cancerous tumors and their metastasis to other parts of the body. Success will result in a clinically applicable, first-ever method for early diagnosis of kidney cancer, moving rapidly toward approval for commercial production.
Human Cancer Immunotherapy Targeting Tumor-Specific Mutational Antigens Identified by Exome Sequencing
Principal Investigator: Robert Schreiber, PhD Description: Recently, members of this team found that cancer genome sequencing can rapidly identify expressed mutations in tumors and showed that some can function as tumor-specific antigens. These mutations target the tumor for immune elimination. This study seeks to extend and validate this novel observation, through new genome sequencing and with attention to the identification of involved proteins. The goal is to develop a method to rapidly and reliably identify the tumor-specific antigens that most effectively induce immune system destruction of tumors.
Principal Investigator: Daniel C. Link, MD Description: In this research, an exciting new therapy will be tested based on a surprising observation made in the Link laboratory. A small clinical trial will determine if treating with G-CSF before starting chemotherapy improves the response rate in patients with multiple myeloma. This research may have applications for other blood cell cancers, such as certain types of acute leukemia.
Principal Investigator: Jay F. Piccirillo, MD, FACS Description: Chemotherapy-induced cognitive impairment, or “chemobrain,” may affect as many as 50% of breast cancer patients. The neural mechanisms in the brain that are responsible for chemobrain are unknown. A novel imaging technique at Washington University, known as resting-state functional connectivity magnetic resonance imaging, measures the functional circuitry or connections between brain regions involved in a particular function. Successful completion of this study will translate basic mechanisms of brain function to chemobrain research, thereby helping to advance the field of cancer survivorship and behavioral research.
Principal Investigator: Audrey S. Shaw, MD Description: Vemurafenib is a new drug recently approved by the FDA for the treatment of melanoma. While this drug has a dramatic effect on melanoma growth, in a large fraction of patients it causes squamous cell carcinoma to develop. This side effect severely limits the effectiveness of the drug treatment. This project proposes to use genome sequencing to understand why vemurafenib causes squamous cell tumors. It is hoped that this will help develop better drugs for the treatment of melanoma.
Principal Investigator: Xiaowei Wang, PhD Description: Invasive cervical cancer is the second most common cancer in women worldwide, resulting in over 300,000 deaths each year. This study focuses on discovering new molecular biomarkers (or, indicators in the body of stress, injury or other change in normal functioning due to disease or the environment) for early identification of cervical cancer patients who would fail standard therapy. In this way, potential individualized therapies can then be applied to these high-risk patients to improve treatment outcome.
Principal Investigators: Zhongsheng You, Ph.D.; Divid Piwnica-Worms, M.D., Ph.D. Description: Cancer is mainly caused by mutations in DNA, which either turn expression of genes on or off or generate protein products with abnormal functions. Nonsense-mediated messenger RNA decay (NMD) is a surveillance system that detects and eliminates defective messenger RNAs that would otherwise produce truncated protein products. Identification of NMD defects in pediatric brain tumors will provide new insights into the underlying molecular defects leading to brain tumors and new potential therapeutic targets. Possible therapies for abnormal NMD may be identified by the small molecule inhibitor screens and studies on NMD pathway genes.
Principal Investigators: Joshua Rubin, M.D., Ph.D.; David Gutmann, M.D., Ph.D. Description: Incomplete understanding of why children get brain tumors hinders their cure. Neurofibromatosis 1 (NF1) is the most common genetic disease associated with childhood brain tumors (gliomas). The goal of this project is to better understand why some children with NF1 get gliomas and others do not. To achieve this goal we will examine subtle variations in DNA known as polymorphisms. Success in these aims will improve diagnostics and therapeutics for children with brain cancer as early as the next 10 years.
Principal Investigator: Megan Cooper, M.D., Ph.D. Description: Pediatric autoimmune diseases such as systemic lupus erythematosus are often difficult to diagnose and can have devastating long-term effects on health including chronic arthritis organ damage cardiovascular disease, and mortality. This project will investigate whether pediatric patients with other autoimmune diseases that share clinical features of ALPS, including systemic lupus erythematosus and mixed connective tissue disease, have abnormal immune cells with somatic genetic defects. This research will lead to new approaches for diagnosis, monitoring, and treatment of these diseases within the next 10 years.
Principal Investigator: Martha Bhattacharya, Ph.D. Description: Pediatric cancer patients are routinely prescribed chemotherapy including the drug vincristine. While vincristine is effective in disrupting cell division and halting tumor growth, it comes with the serious side effect of peripheral nerve damage. This damage can cause loss of motor and sensory function as well as intense pain. We have identified a number of critical molecular pathways used by vincristine and other chemotherapy drugs to cause axonal damage. This work will enhance our mechanistic understanding how peripheral neuropathy develops in pediatric and adult cancer patients following exposure to chemotherapy drug and how this can be prevented.
Principal Investigator: Lee Ratner, MD, PhD Description: Ratner will investigate the role of a virus in the development of prostate cancer. His research has the potential to make strides toward new therapies for the treatment and prevention of prostate cancer.
Principal Investigator: Ron Bose, MD, PhD Description: Between 20-25 percent of all newly diagnosed instances of breast cancers are ductal carcinoma in situ (DCIS), which are small and contained tumors. Standard treatment can be aggressive, with more side effects than necessary in cases where tumors would not have spread. Dr. Bose’s goal is to determine which DCIS lesions are most likely to spread and invade other tissues, in order to treat those lesions specifically, which would result in better outcomes for patients with fewer side effects.
Principal Investigator: Lynn Cornelius, MD Description: In a unique collaboration, dermatologist Cornelius is working with biomedical engineer Wang to develop a handheld imaging device that will improve melanoma detection at an early stage (when surgery has the greatest chance of cure) and measure a tumor’s depth and volume (a technology not currently available). Their goal is to bring this device to the bedside, where it may impact the survival of melanoma patients.
Principal Investigator: Graham Colditz, MD, DrPH Description: Diet during adolescence may have effects on such early indictors of breast cancer as rapidly-spreading benign breast disease, and also on some characteristics of normal appearing breast tissues. A study by Graham Colditz, MD, DrPH will measure these effects, and how changes in diet at this critical time in growth and development can reduce the likelihood of a person developing breast cancer.
Principal Investigator: Ying Liu, MD, PhD Description: Dr. Liu’s team will compare proteins expressed in pure ductal carcinoma in situ (DCIS) legions with those expressed in the components of DCIS associated with invasive breast cancer (IBC), for which DCIS can be a precursor. Their data will have profound implications for estimating an individual’s risk of developing IBC and for targeting cancer intervention therapies for those patients.
Principal Investigator: Shelia Stewart, PhD Description: Cancer is not only the result of mutations within cancer cells, but also a result of age-related changes in the surrounding noncancer cells. Shelia Stewart, PhD and her team are working to uncover how older, noncancerous cells impact the development of breast cancer, with the goal of uncovering targets for therapy within the noncancerous cells because they are less likely to be resistant to therapies than the tumor itself. This research will ultimately impact the development of anti-cancer drugs.
Principal Investigator: Farrokh Dehdashti, MD Description: Patients with hormone sensitive, operable breast tumors are often treated with endocrine therapy (a type of hormone therapy) to shrink the tumor. However, only slightly more than 50 percent of patients who receive this therapy respond to it. Farrokh Dehdashti, MD and her team will use existing imaging technology in a novel way to more accurately predict which patients will most likely respond to endocrine therapy, and which patients will not, to ultimately improve personalized treatment plans for breast cancer patients.
Principal Investigator: Loren Michel, MD Description: Basal-like breast cancer is a highly lethal form of the disease, and effective therapies are lacking. Loren Michel, MD and his team will study how blocking two specific receptors (structures on a cell that receive and bind it to substances) may effectively kill basal-like breast cancer cells. Their study will lay the foundation for a clinical trial of a new treatment option for basal-like breast cancer.
Principal Investigator: Ying Liu, MD, PhD Description: Dr. Liu’s team will compare proteins expressed in pure ductal carcinoma in situ (DCIS) legions with those expressed in the components of DCIS associated with invasive breast cancer (IBC), for which DCIS can be a precursor. Their data will have profound implications for estimating an individual’s risk of developing IBC and for targeting cancer intervention therapies for those patients.
Principal Investigator: Joel Garbow, PhD Description: Radiation therapy is an important part of treatment for patients with brain tumors. However, radiation necrosis (a severe type of injury to normal, healthy brain tissue that occurs several months following radiation treatment) can negatively impact a patient’s life-and distinguishing necrosis from a recurrent tumor is a significant challenge. Both issues have critical consequences for patient treatment and outcomes. Joel Garbow, PhD and his team will develop magnetic resonance imaging (MRI) tools and use experimental MRI techniques to clarify the understanding of the brain tissue changes that follow radiation therapy of the brain. The ability to monitor these changes non-invasively, and to prevent and reduce these changes with therapeutic interventions, will lead to better clinical outcomes and improved quality of life for patients with brain tumors.
Principal Investigators: Jeffrey Leonard, MD and Joshua Rubin, MD, PhD Description: With pediatric brain tumors, the extreme difficulty in obtaining and culturing brain tumor cells has severely hampered research. In 2007, the Children’s Discovery Institute funded the Pediatric Brain Tumor Data Bank to overcome that limitation. With their Institute grant, pediatric neurosurgeon Leonard and pediatric neuro-oncologist Rubin created a tissue repository of native brain tumor tissue that is coupled with individual patient data. This continuously monitored specimen-patient linked data, unique to the Children’s Discovery Institute Data Bank, will become enormously valuable as understanding of children’s brain tumors evolves.
Principal Investigator: Joshua Rubin, MD, PhD Description: The investigators will determine how the presence of a brain tumor changes the brain around it and what the differences are in the response to a brain tumor between different regions of the brain. Defining these differences will extend understanding of this critical mechanism for the regulation of brain tumor growth and will identify targets for a novel approach to brain tumor therapy that addresses the functions of the surrounding brain rather than the tumor itself.
Principal Investigators: Todd Druley, MD, PhD and Robi Mitra, PhD Description: Druley and Mitra have begun the enormous task of developing a way to find and quantify all of the alternative forms of a given gene – even those that occur in less than one percent of humans. The new tools the team developed will help identify a variety of rare, but important genetic variants related to the disease and help to answer the question of why children get cancer.