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.
Principal Investigator: Tim Ley, MD Goal: Pre-PPG/SPORE Recommendation. To use genome sequencing to fully address why some acute myeloid leukemia patients do well, and others poorly, as well as study the mechanisms by which some leukemia cells can evade current therapies to cause relapse. Description: Acute myeloid leukemia (AML) is a devastating form of blood cancer that most commonly occurs in older patients (average of 67 years); the average survival is less than a year for most older patients. Over the past decade, we and others have used new methods to sequence all of the genes in the leukemia cells of AML patients, and have discovered nearly all of the mutations that can initiate the disease, and cause its progression. However, our knowledge base is still incomplete. We still do not fully understand why some patients do well, and others poorly, and we do not fully understand the mechanisms by which some leukemia cells can evade our current therapies to cause relapse. Here, we propose to use more sophisticated sequencing studies to fully address these questions. It should allow us to better define risk at presentation, and tailor therapies more precisely for each patient.
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.
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.
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.
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.
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.
|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.
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.
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.
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.
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.
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.