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Funded Research Projects from PTC 2015

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The Siteman Cancer Center Awards

Project: Regulation of Glioblastoma Stem-Like Cells by CDC20-Anaphase-Promoting Complex
Principle 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.
Project: Deactivating the Innate Immune Defense Mechanism of Pancreatic Cancer
Principle 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.
Project: Exploring T cell Diversity as a Novel Mechanism for Cancer Immunotherapy
Principle 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.
Project: Axonal Maintenance for Prevention of Chemotherapy-Induced Peripheral Neuropathy
Principle 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.
Project: Tumor-Environment Communication Regulating Metastasis
Principle 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.
Project: Characterizing the Effects of Sexual Dimorphism on Glioma Metabolism
Principle 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.
Project: Siteman Cancer Center Breast Cancer SPORE
Principle 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.
Project: Functional Genomics of Ovarian Cancer Metastasis
Principle 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.
Project: Phase IB Clinical Trial of a Candidate Breast Cancer Prevention Vaccine
Principle 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.
Project: Designing Novel Therapeutic Approaches to Pancreatic Ductal Adenocarcinoma (PDAC)
Principle 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.

St. Louis Children's Hospital Awards

Project: MRI-guided Laser Heat Ablation to Induce Blood Brain Barrier Breakdown in Pediatric Brain Tumors
Principle 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.
Potential Impact: This study could pave the way for novel therapeutic approaches that synergize MLA with chemotherapy to improve the prognosis of difficult-to-treat pediatric brain tumors.
Project: Sex-specific Super Enhancer Activity in Glioblastoma
Principle 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.
Potential Impact: Glioblastoma causes significant morbidity in infants. This approach is promising because novel targets identified through the study of sex differences are likely to both be effective and have fewer side effects, since modulation of these targets already happens in females.
Project: A Phase-I Trial of Familial Haploidentical Nonmyeloablative Bone Marrow Transplantation in Children
Principle 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.
Potential Impact: Hematopoietic cell transplantation can cure SCD in the majority of those with severe symptoms. Haploidentical family donors are always available to SCD patients. This novel pilot trial will thus investigate a curative option for a serious childhood disorder. This approach could also potentially be applied for HCT in pediatric cancer patients.
Project: Intraoperative Real-time Fluorescences Image-guided Resection of Pediatric Brain Tumors
Principle 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.
Potential Impact: This approach will enable more accurate surgery, potentially decreasing short-term post-surgical neurologic deficits and increasing the extent of tumor resection for both high- and low-grade pediatric brain tumors. This may increase disease-free survival and decrease serious side effects from chemotherapy and radiation therapy used to treat residual tumor in pediatric patients.

Funded Research Projects from PTC 2014

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The Siteman Cancer Center Awards

Project: Functional Genomics of Ovarian Cancer Metastasis
Principle 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.
Project: Designing Novel Therapeutic Approaches to Pancreatic Ductal Adenocarcinoma (PDAC)
Principle 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.
Project: Assessment of Functional Status of Estrogen Receptors in Breast Cancer by PET
Principle 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.
Project: FDOPA-PET/MRI for the Pre-operative Evaluation of Gliomas
Principle 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.
Project: Immune-Based Therapies for AML
Principle 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.
Project: Mechanisms of Gastrointestinal Tumorigenesis
Principle 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.
Project: DNA Replication, Nuclear Architecture and Genome Stability
Principle 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.
Project: Memory-like natural killer (NK) cells for cancer immunotherapy
Principle 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.
Project: Targeting Focal Adhesion Kinase to Render Pancreatic Cancer Responsive to Immunotherapy
Principle 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.

St. Louis Children's Hospital Awards

Project: Improving Minimal Residual Disease Surveillance Of Pediatric AML Via Error-corrected Sequencing
Principle 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:
  1. Extend ECS to test multiple different recurrently mutated genes in AML.
  2. Apply ECS-MRD testing to approximately 150 remission pediatric AML samples with MRD status and correlate MRD status with outcome.
  3. 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.
Project: Understanding Mechanisms Of Alkylation Chemoresistance In Pediatric Glioblastoma
Principle 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:
  1. 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.
  2. 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.
Project: Targeting The Abnormal Chromatin State Of Pediatric Brain Tumors
Principle 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:
  1. 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.
  2. 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.

Funded Research Projects from PTC 2013

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2013 Research Supported by the Cancer Frontier Fund at the Siteman Cancer Center Through The Foundation for Barnes-Jewish Hospital

Project: Patient-specific mutation-directed immunotherapy for melanoma
Principle 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.
Project: Epigenetic Modulation of GvHD and GvL
Principle 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.
Project: Role of Notch Signaling in AIDS-Associated Kaposi's Sarcoma
Principle 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.
Project: Phase 1B Clinical Trial of a Candidate Breast Cancer Prevention Vaccine
Principle 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.
Project: Development of a Multigene Assay for Predicting Oral Cancer Metastasis
Principle 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.
Project: Immune Based Therapies for AML
Principle 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.
Project: Tamoxifen to Treat Barrett's Metaplasia
Principle 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.

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

Project: Functional Characterization of Rare Congenital Variation in Infantile Leukemia (IL)
Principle 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.
Project: The Developmental Changes in Stem Cell Self-renewal Mechanisms and Their Role in Leukemogenesis
Principle 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.
Project: Nextgen Deep Sequencing In Post-transplant Lymphoproliferative Disorders (PTLD)
Principle 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.

Funded Research Projects from PTC 2012

The Siteman Cancer Center Individual and Team Awards

Project: Defining Molecular Targets on Micro Metastatic Disease in Breast Cancer
Principle 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.
Project: Epigenetic Modulation of GvHD and GvL
Principle 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.
Project: Patient-specific mutation-directed immunotherapy for melanoma
Principle 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.
Project: Exploring mechanisms to treatment resistance to improve outcomes in pancreatic cancer
Principle 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.
Project: Identifying Mechanisms of Metastasis to Improve Outcomes in Metastatic Colorectal Cancer
Principle 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.
Project: Using Heat Ablation to Disrupt the Blood Brain Barrier to Enhance Delivery of Chemotherapy in the Treatment of Recurrent Glioblastoma
Principle 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.

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

Project: Altered Epigenetics as a Driver of T-cell Acute Lymphoblastic Leukemia
Principle 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.
Project: Targeting Nucleolar Protein Interactions in Pediatric Gliomas
Principle 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.

Funded Research Projects from PTC 2011

The 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; 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.
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 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.
Project: Validation of Biomarkers for Kidney Cancer Diagnosis and Monitoring of Metastatic Disease
Principle 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.
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 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.
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: 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.
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.; 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.
Project: Sexually Dimorphic cAMP Signaling Impacts the Rate of Brain Tumors in Prepubertal Boys & 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. 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.
Project: Molecular Strategies to Block Peripheral Neuropathy in Mouse Models of Vincristine Neurotoxicity
Principle 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.

Funded Research Projects from PTC 2010

The Siteman Cancer Center Individual and Team Awards

Project: Role of XMRV Retrovirus Infection in Prostate Cancer
Principle 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.
Project: Molecular Predictors of Ductal Carcinoma In Situ Progression To Invasive Breast Cancer
Principle 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.
Project: Melanoma Management by in Vivo Laser-Induced Photoacoustic Microscopic Imaging
Principle 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.
Project: Adolescent Diet and Risk of Proliferative Benign Breast Disease
Principle 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.
Project: Characterization of the Stroma from Ductal Carcinoma in Situ and Progression
Principle 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.
Project: Breast Cancer Development in the FASST Mouse
Principle 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.
Project: Prediction of Response to Endocrine Therapy in Premenopausal Women with FFNP-PET Imaging and PEPI
Principle 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.
Project: Role of Notch-EGFR pathway cooperativeity in basal-like breast cancer
Principle 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.
Project: Characterization of the Stroma from Ductal Carcinoma in Situ and Progression
Principle 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.
Project: Imaging Biomarkers for Radiation-Induced Necrosis
Principle 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.

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

Project: The Pediatric Brain Tumor Data Bank
Principle 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.
Project: Characterization of the Brain Tumor Microenvironment Proteome
Principle 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.
Project: Why Do Children Get Cancer?
Principle 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.