Research related to breast, prostate and lung cancers are among the 11 projects that will benefit from $1.8 million in new grants announced by Siteman Cancer Center through its Siteman Investment Program. The goal of the grants is to support and accelerate the pace of innovation in cancer research.
The money awarded comes from a variety of sources: Pedal the Cause annual bike challenge and Illumination gala, through the Cancer Frontier Fund at the Foundation for Barnes-Jewish Hospital; Swim Across America – St. Louis, the Fashion Footwear Association of New York; the National Cancer Institute; and the Barnard Trust.
The research projects are described below.
Title: Rescue of HNF4a levels restores hepatocyte function and prevents end-stage liver disease and cancer in patients with impaired telomere maintenance
Goal: To generate much needed molecular knowledge to prevent failure of liver cells and ultimately develop novel treatment strategies against liver cancer, which currently has no cure
Description: Chromosomes represent DNA molecules that store genetic information inside our cells. The “caps” of each of these chromosomes are composed of repetitive DNA sequences that are essential to protect chromosomes from degradation, similar to the role of aglets in shoelaces. Due to different reasons, telomeres shorten every time a cell divides, and when telomeres reach a critical short length they induce a growth arrest response that prevents cells to further divide. This response compromises the ability of tissues and organs to recover after damage. On the other hand, if this telomere-controlled cellular division response is bypassed, cells could have uncontrolled proliferation, which promotes tumor formation. Therefore, precise control of telomere length is essential and has to be tightly regulated. In fact, we now know that patients with severe liver disease and cancer have abnormal telomere maintenance, which contributes to the progression and the severity of these devastating conditions. Our goal in this project is to use novel cellular models that our laboratory has developed to elucidate how impaired telomere regulation contributes to liver failure and cancer, and find new mechanisms to prevent that. We are confident our results can lead to the development of novel therapies aimed at preventing failure of liver cells and the progression of end-stage liver disease and cancer. Our ultimate goal is to generate much needed molecular knowledge to devise novel treatment strategies against this disease, which currently has no cure.
Title: Reprogramming epithelial stem cells in triple-negative breast cancer
Principal investigator: Michael Holtzman, MD, the Selma and Herman Seldin Professor of Medicine, a professor of cell biology and physiology and director of the Division of Pulmonary and Critical Care at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To further study a new cause of triple-negative breast cancer and a new drug candidate in cell and animals models and ultimately transition this drug into human clinical trials
Description: This proposal addresses the challenge of understanding and treating breast cancer, which is projected for 41,000 deaths for 2018 despite any of the current therapeutic approaches. The project is specifically focused on the 15 to 20 percent of breast cancer that cause these deaths, generally because they are negative for hormone and growth factor receptors and are therefore not specifically targeted by any current treatments. Here we will pursue our discoveries of a new cause of severe forms of breast cancer and a new drug candidate that corrects this mechanism in cell and animal models. We will use these models to validate our proposed pathway to breast cancer and will optimize the effectiveness and safety of our new drug for blocking breast cancer. These results will form the basis of a new paradigm for breast cancer and the next and final phase of studies needed for clinical trials in humans with breast cancer.
Title: The role of pericellular serine proteases in tumor progression and resistance to anticancer therapy
Principal investigator: James Janetka, PhD, an associate professor of biochemistry and molecular biophysics at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To test whether small molecule protease inhibitors developed in his lab are effective at overcoming and preventing resistance to anticancer therapy in lung cancer animal models
Description: While many cancer patients initially respond to targeted anticancer therapy, these drugs eventually stop working, which is one of the biggest challenges in the treatment of lung cancer patients. Hepatocyte growth factor (HGF) allows the growth of tumor in the presence of anticancer therapy. Levels of HGF are increased in the blood and tissues of lung cancer patients that do not respond to targeted therapy with shrinking of the tumors. Currently, there is no approved drug that would block the activity of HGF. We have discovered unique inhibitors of the three serine proteases, HGF-Activator, matriptase and hepsin, which prevent the activation of HGF. We have shown that our lead compound VD2173 significantly improves the response of human cancer cell lines to clinically used therapeutic agents. The goal of this project is to demonstrate that VD2173 both overcomes and prevents resistance to targeted therapy in mouse models of lung cancer; a necessary step in the preclinical development of VD2173 as a new drug for lung cancer patients.
Title: Defining Transcriptional Regulators of Melanoma Initiation
Principal investigator: Charles Kaufman, MD, PhD, an assistant professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To better understand how a key gene in melanoma is controlled and its role in the earliest mechanisms regulating the formation of melanoma and ultimately identify new potential treatment targets
Description: While a number of remarkable new treatments have recently become available for melanoma skin cancer, these therapies are not curative for most patients whose disease has spread. If we better understood how melanoma begins at a molecular level, then we could detect these changes earlier when melanoma is curable with surgery. Further, we could also aim to interrupt this process with a drug, so the melanoma never gets started. The goal of this proposal is to understand how a key gene in melanoma, called sox10, is controlled. Without sox10 function, most melanoma tumors do not survive, and turning up sox10 levels in normal pigment cells, called melanocytes, appears to be an important early step in causing melanoma to form. We aim to uncover the signals and proteins in the melanoma cell that control how much sox10 is made and when is it increased. Understanding this control of sox10 offers a window into the earliest mechanisms regulating the initial formation of melanoma and thus new potential treatment targets.
Title: Cooperating mutations and resistance to FLT3-ITD inhibition in pediatric acute myeloid leukemia
Principal investigator: Jeffrey Magee, MD, PhD, an assistant professor of pediatrics at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To better understand the biology of pediatric leukemia cells that are left after cancer therapy and to try to identify the genes that enable these leukemia cells to resist such cancer treatment
Description: Acute myeloid leukemia (AML) accounts for approximately 25 percent of childhood leukemias. AML is often difficult to treat, and even successful treatments can leave children with lifelong disabilities. Childhood AML is often caused by different mutations than adult AML. This is not a hard and fast rule – some mutations are found in both ages – but certain mutations skew heavily toward the pediatric population. This raises the question of whether drugs that target mutant proteins might have different effects on childhood and adult AML. We propose to test this possibility. We are particularly interested in understanding the biology of leukemia cells that persist after therapy. Our preliminary data suggest that AML cells may have fundamentally different patterns of DNA organization when they persist in children as compared to adults. We will identify genes that sustain drug resistant childhood AML cells with the goal of developing new treatment strategies.
Title: Alkylating chemotherapies promote heart failure by targeting tissue resident cardiac macrophages
Principal investigator: Nima Mosammaparast, MD, PhD, an associate professor of pathology and immunology at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To study the reasons behind the sensitivity of cardiac cells to common chemotherapeutics, to be able to come up with effective means to counter heart failure in cancer survivors
Description: While many commonly used chemotherapies used in cancer can be effective for the tumor itself, they cause long-term side effects in survivors. It is well-established that cancer survivors often develop heart disease or heart failure as a result of the chemotherapeutics they are given. However, the molecular and cellular mechanisms that cause this in the heart are not known. We propose that certain cells that reside in the heart, called cardiac macrophages, are particularly sensitive to commonly chemotherapeutics used for cancer treatment. We propose to study the reasons behind this sensitivity, to be able to come up with effective means to counter heart failure in cancer survivors.
Title: A single-arm phase II study with a safety lead-in of magnetic resonance-guided hypofractionated adaptive radiation therapy with concurrent chemotherapy and consolidation durvalumab for inoperable stage IIB and IIIA non-small cell lung cancer
Principal investigator: Gregory Vlacich, MD, PhD, an assistant professor of radiation oncology at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To study through a clinical trial whether higher doses of radiation delivered safely with chemotherapy using a unique, cutting-edge, MRI-guided radiation delivery system followed by standard-of-care immunotherapy will improve tumor control and survival in non-small cell lung cancer
Description: In the U.S., non-small cell lung cancer is the leading cause of cancer-related death. For individuals with non-metastatic, but advanced disease, a large percentage who receive the current standard therapy continue to fail treatment at or near the original sites of disease, and this is directly correlated with worse survival. New approaches to reduce these failures are necessary to improve the chance for cure. In our clinical trial, we explore the use of a unique, cutting edge, MRI-guided radiation delivery system to improve tumor control by delivering significantly higher doses of radiation per treatment than conventional radiation. Through improved image resolution with MRI and real-time treatment adaptation, higher dose can be achieved with this system through enhanced protection of organs surrounding the tumor. We propose that higher doses of radiation delivered safely with chemotherapy using our MRI-guided system followed by standard-of-care immunotherapy will improve tumor control and survival.
Title: Role of a novel IL-7 agonist, rhIL-7hyFc, in immune reconstitution in patients with gliomas
Principal investigator: Jian Campian, MD, PhD, an assistant professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To better understand the mechanisms of a new drug currently in clinical trials that is designed to restore the immune status in patients with gliomas receiving radiation and chemotherapy
Description: Impaired immune system is common in cancers such as malignant brain tumors. The current standard of radiation and chemotherapy can decrease the numbers of immune cells (lymphocytes). Decreased lymphocytes is associated with shorter survival for patients with a variety of cancers. This study is the first to test if a novel interleukin-7 analogue, rhIL7hyFc, can increase lymphocytes and restore immune status in patients treated with standard radiation and chemotherapy for their brain tumors. The clinical trial is ongoing. Preliminary data suggest rhIL-7hyFc can increase lymphocytes. The current proposal is to perform novel correlative studies to better understand the mechanism and the full impact of rhIL-7hyFc treatment on immune modulation in brain tumors. The findings from this study will have an impact on the use of rhIL-7hyFc in combination with other immunotherapy treatments such as checkpoint inhibitors, vaccines or oncolytic virus in the treatment of malignant brain tumors.
Title: Personalized neoantigen vaccine immunotherapy for prostate cancer
Principal investigator: Russell Pachynski, MD, an assistant professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To analyze immune responses from metastatic prostate cancer patients currently in a clinical trial designed to test a combination of immunotherapies, including a personalized vaccine
Description: Despite the success of immunotherapy in many tumors, response rates in prostate cancer have been disappointingly low. The current frontline treatment for metastatic prostate cancer slows down the disease and usually puts patients into a temporary “remission” of sorts, but does not cure it, and lethal, resistant prostate cancer then recurs. Our study uses a combination of immunotherapies given to patients after initiation of standard frontline therapy in order to stimulate the immune system to eradicate the residual prostate cancer. We are utilizing a PSA-based viral vaccine in combination with two other immune-stimulating drugs. We then use a personalized vaccine made from each patient’s tumor tissue, termed a “neoantigen” vaccine, also in combination. Over the treatment course, we will collect samples to analyze immune responses to this combination immunotherapy strategy and correlate these with patient outcomes. This is the first trial of this combination of immunotherapies and personalized vaccines in metastatic prostate cancer patients.
Title: Targeting LXR regulation of prostate cancer immunometabolism
Principal investigator: Colin Flaveny, PhD, an assistant professor of pharmacology and physiology at Saint Louis University School of Medicine and a research member of Siteman Cancer Center
Goal: To determine the efficacy of a newly developed drug designed to make metastatic prostate cancer vulnerable to existing cancer immunotherapy treatments, which are notoriously ineffective
Description: Prostate cancer is the most diagnosed and leading cause of cancer-related death in men, except for skin cancer. The vast majority of prostate cancer patients succumb to recurrent metastatic disease, which is normally resistant to treatment. Therefore, there is an urgent need to develop new therapies that disrupt metastatic prostate cancer growth in order to save lives. One approach to developing effective treatments is to target the biological processes that allow prostate cancer cells to grow unchecked. Prostate cancer cells are uniquely dependent on fat or lipid production, which is used to fuel growth, facilitate chemotherapy drug-resistance and allows cancer cells to evade detection and destruction by the immune system. Clinically used treatments that harness the tumor-killing properties of the immune system, such as immune-checkpoint blockade inhibitors, have been very successfully used to treat lung and skin cancer. Unfortunately, these drugs are ineffective at treating prostate cancer. We have discovered that lipids released from tumor cells suppress the activity of tumor-killing immune cells by activating the Liver-X-Receptor (LXR), a key regulator of immune function. Therefore, we hypothesized that LXR can be targeted to induce immune-destruction of prostate tumors. We have successfully developed an LXR-targeting drug that stimulates immune cells to destroy prostate tumors by preventing tumor lipids from inhibiting immune function. This project is designed to comprehensively determine if LXR drugs are effective treatments by profiling their activity in clinically relevant mouse models that recreate all aspects of prostate cancer progression in humans. We will also determine if our LXR drugs can be used to sensitize prostate tumors to clinically used immune-checkpoint blockade inhibitors. Our investigations should lead to the development of an exciting novel class of prostate cancer drugs that potently disrupts tumor growth and reduces prostate cancer mortality.
Title: Lysine acetylation of human histone deacetylase 3 as a new cancer target
Principal investigator: Jinsong Zhang, PhD, an associate professor of pharmacological and physiological science at Saint Louis University School of Medicine and a research member of Siteman Cancer Center
Goal: To study a recently discovered mechanism in cancer cells that can switch on and off genes that suppress tumors and genes that promote tumors and ultimately explore its use as a new cancer target and new class of cancer drugs
Description: Cancers result from altered levels of tumor suppressor genes (genes that suppress tumors) and oncogenes (genes that promote tumors). Histone deacetylase 3 (HDAC3) can reduce gene levels, and its inhibitors are used to treat cancers by increasing tumor suppressor levels. However, these inhibitors are not specific to HDAC3 and therefore can result in unwanted side effects, preventing their use in most cancers. They also have a limited ability to treat cancers induced by oncogenes. We have recently discovered a new HDAC3-specific mechanism that can switch HDAC3 on and off for different genes, including tumor suppressors and oncogenes. This proposal will further study this mechanism in cancer cells, determine the molecular basis, and explore its use as a new cancer target, both to increase tumor suppressors and decrease oncogenes. The ultimate goal is to develop a new class of cancer drugs with improved specificity and enhanced abilities to treat various cancers in the coming era of personalized medicine.