Current Research

Siteman Cancer Center Individual and Team Awards

Project: Exploring mechanisms of treatment resistance to improve outcomes in pancreas cancer
Principle Investigators: David C. Linehan, MD; David 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 four to six 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 novel therapies.
Project: Investigations of HER2 Mutation in HER2 Negative Breast Cancer
Principle 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 two-part 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 further, larger trials and, some day, treatment access for all patients with this type of breast cancer to the increasing numbers of anti-HER2 medications.
Project: Validation of Biomarkers for Kidney Cancer Diagnosis and Monitoring of Metastatic Disease
Principle Investigators: Jeremiah Morrissey, PhD
Description: When diagnosed by symptoms, patients with the two predominant forms of kidney cancer (clear cell and papillary) have poor outcomes. However, when caught earlier, patient survival rates exceed 70%. There is currently no method of screening for kidney cancer and tumors are usually discovered as a byproduct of other medical investigations. This team will screen large groups of patients to determine if certain biomarkers can correctly identify and predict cancerous tumors and their metastasis (spread) 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.
Project: Human Cancer Immunotherapy Targeting Tumor-Specific Mutational Antigens Identified by Exome Sequencing
Principle 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 thus target the tumor for immune elimination. This study seeks to extend and validate this novel observation, through state-of-the-art genome sequencing and with particular attention to the identification of involved proteins. The goal is to develop a method to rapidly and reliably identify those tumor-specific antigens that most effectively induce immune system destruction of tumors.
Project: Targeting the Bone Marrow Environment in Multiple Myeloma
Principle 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.
Project: Neurobiology of Chemotherapy-Induced Cognitive Impairment
Principle 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.
Project: Understanding the Mechanism of BRAF Inhibitors in the Induction of Squamous Cell Carcinoma
Principle Investigator: Andrey 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 a different type of skin tumor, squamous cell carcinoma, to develop. This unfortunate side effect severely limits the effectiveness of the drug treatment. This project proposes to use genome sequencing (or, detailed analysis of the exact sequence of genes occurring in a tumor) to understand why vemurafenib causes squamous cell tumors. It is hoped that this will help develop better drugs for the treatment of melanoma.
Project: MicroRNA Expression Signatures to Predict Cervical Cancer Outcome
Principle 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.

The Children's Discovery Institute at St. Louis Children's Hospital Awards

Project: Targeting An RNA Surveillance Pathway In Pediatric Cancer
Principle Investigators: Zhongsheng You, Ph.D.; David Piwnica-Worms, M.D., Ph.D.
Description: Brain tumors in children represent a major challenge for cancer treatment. 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 as well as new potential therapeutic targets. In turn, possible therapies for abnormal NMD may be identified by the small molecule inhibitor screens and basic studies on NMD pathway genes. If successful, clinical translation could occur as early as within 10 years.
Project: Sexually Dimorphic cAMP Signaling Impacts the Rate of Brain Tumors in Prepubertal Boys and Girls
Principle 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.
Project: Investigation of Somatic Defects in Patients with Autoimmune Diseases
Principle 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. Dr. Cooper's 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.We anticipate that this research will lead to new approaches for diagnosis, monitoring, and treatment of pediatric autoimmune diseases within the next 10 years.
Project: Molecular Strategies to Block Peripheral Neuropathy in Mouse Models of Vincristine Neurotoxicity
Principle Investigators: 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. These results could be applied to the care of cancer patients within the next 5 - 10 years.