Research on acute myeloid leukemia and pancreatic cancer are among the nine projects that will benefit from $2 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; Fashion Footwear Association of New York; National Cancer Institute; and Barnard Trust.
The research projects are described below.
Title: The Role of Interferon Gamma Signaling in the Clonal Evolution of Pre-Leukemic Stem Cells
Principal investigator: Grant Challen, PhD, an assistant professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To understand how mutant stem cells react to specific signals from the bone to become leukemic cells, and to identify methods to eliminate the mutant cells before they cause cancer
Description: As we age, stem cells that generate blood and bone marrow accumulate genetic mutations. Some of these mutations occur in cancer-causing genes, which allow the mutant cells to overtake the bone marrow. We recently showed that virtually all people older than 50 have at least one stem cell with a cancer-associated genetic mutation. This observation has led us to ask, if these mutations are happening in our bone marrow all the time as we age, why doesn’t everyone eventually develop cancer? We propose that specific signals from the bone are required for these mutant cells to generate cancer, and have identified a component of the natural inflammatory response that promotes survival of stem cells with cancer-causing mutations. The goal of this project is to understand how mutant stem cells react to this signal, and to identify methods to eliminate them before they can cause cancer.
Title: IFNγR and IL6R Signaling Pathways as Therapeutic Targets to Prevent Graft-versus-Host Disease While Preserving Graft-versus-Leukemia
Principal investigator: Jaebok Choi, PhD, an assistant professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To determine how two proteins (IFNgR and IL6R) cause graft-versus-host disease (GvHD) after a bone marrow transplantation in leukemia patients, and to test whether drugs that inactivate these two proteins can prevent GvHD without interfering with the killing of leukemia cells
Description: The most effective treatment for many patients with leukemia or other blood cancers is to administer bone marrow transplants containing immune cells obtained from a healthy donor whose immune system is closely matched and thus should not “see” the cancer patient’s body as foreign and thus should not attack it. Although these cells can effectively kill the patient’s cancerous cells, in about 50 percent of patients the donor cells still attack the patient’s skin, intestines, lung and liver in a phenomenon known as graft-versus-host disease (GvHD) because it recognizes the patient as “foreign.” GvHD can be severely debilitating or even fatal and is the primary obstacle to successful transplantation. We have identified two proteins (IFNgR and IL6R) that cause GvHD. We have also demonstrated that genetically inactivating these proteins eliminates GvHD, yet the healthy immune cells can still kill the leukemia cells in mouse models. In this proposal, we will determine how these proteins cause GvHD and test whether drugs that inactivate these proteins prevent GvHD without interfering with the killing of leukemia cells. Such drugs would revolutionize bone marrow transplantations, enhance patient’s quality of life and improve survival.
Title: The Impact of Macrophage Origin on the Pathogenesis of Pancreatic Cancer
Principal investigator: David DeNardo, PhD, an associate professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To gain an understanding of how to target a subset of immune cells that are responsible for creating a scar-like “armor” thought to protect pancreatic cancer cells and ultimately improve outcomes for pancreatic cancer patients
Description: Pancreatic cancer has a dismal prognosis, with only 8 percent of patients living past five years. One of the major challenges to treating pancreatic cancer is that current therapies such as chemotherapy or radiation therapy are not as effective in pancreatic cancer compared to other cancers. This difference may be due to the unique environment in which pancreatic cancer cells reside. The pancreatic tumor environment closely resembles highly fibrotic scar-like tissue. This scar-like environment is thought to provide a biological “armor” for pancreas cancer cells to survive and even thrive in during therapy. Thus, new drugs that can break through this this scar-like “armor” would be highly desirable as treatments of pancreatic cancer. We have discovered a unique subset of immune cells, called macrophages, which create this scar-like “armor.” Thus, we believe these immune cells represent an excellent therapeutic target. However, the classical assumption is that macrophages in tumors come from the bone marrow. Based on this assumption several ongoing clinical trials are targeting macrophage through their recruitment from blood. However, we have found that the macrophages that regulate the scar-like “armor” of pancreatic cancer are ancient cells that entered the pancreas during development of the fetus and the rules that govern their growth are different than those that come from the bone marrow. Thus, these studies will seek to understand how to target this subset of macrophages to improve outcomes for pancreatic cancer patients.
Title: Development of an Immunocompetent Autochthonous Model of Glioblastoma
Principal investigator: Gavin Dunn, MD, PhD, an assistant professor of neurological surgery, neurology and pathology/immunology at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To develop a better understanding of how the immune system recognizes brain tumors and to find a way to study immune response to recurrent tumors
Description: Glioblastomas are the most aggressive brain cancer, with an average length of survival of 15 months after diagnosis. Although successful in other cancers, treatments that harness the immune system to fight tumors, or immunotherapies, are not yet as effective in glioblastoma. Key barriers include our limited understanding of immune responses to brain tumors when they first form and when they come back after standard treatment. In fact, recurrent tumors should be more responsive to immunotherapies because they contain major genetic changes that make them more susceptible to immune attack. Indeed, one could liken this to the removal of a disguise. These genetic changes should allow the immune system to “see” the tumor cells, but the immune system does not kill the tumor cells. The major question is, given the fact that the immune system is designed to kill these cells, why doesn’t it do so? This question is difficult to study using current brain tumor lab models. Our goal is to use a new lab model of brain cancer in mice that we developed to better understand how the immune system recognizes brain tumors and to find a way to study immune responses to recurrent tumors. This work will help shape how we can enhance immunotherapies for glioblastoma patients.
Title: Discovering the Role of Phosphorylation in the Pleckstrin Homology Domain
Principal investigator: Kristen Naegle, PhD, an assistant professor of biomedical engineering at Washington University in St. Louis and a research member of Siteman Cancer Center
Goal: To uncover an important basic phenomenon that occurs within normal cell biology and to gain a better understanding of the role it plays in the development of cancer cells
Description: Controlling where proteins are in the cell is vital to whether they perform the right function in the right place. There is a large class of proteins in human cells (lipid-binding proteins) that get recruited to the right place because they can interact with lipids found on the surfaces of the cell and many structures within the cell (i.e. membranes). This project will test a novel idea that a normal chemical process that occurs within cells (protein modification) can control the interaction of lipid-binding proteins with lipids in cell membranes. To test this idea, we will compare lipid-binding protein interactions with lipids before and after protein modification. These modifications may prevent proteins from properly interacting with cell membranes and prevent the correct placement of proteins within cancer cells, since increased amounts of protein modifications on lipid-binding proteins are often found in human cancers. We hope to uncover an important basic phenomenon of normal cell biology and better understand the role protein modifications have in cancer. This could ultimately identify new ways in which therapeutics could target and kill cancer cells.
Title: Defining the Role of Long Non-Coding RNAs in Lymphoma Pathogenesis
Principal investigator: Jacqueline Payton, MD, PhD, an assistant professor of pathology and immunology at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To better understand and provide critical insight into the role that a newly discovered class of RNA molecules have in the development of Non-Hodgkin Lymphoma
Description: Non-Hodgkin lymphoma (NHL) is the most common blood cancer in the U.S. Half of all lymphoma patients have disease that is resistant to current treatments, thus there is an urgent and unmet need for new therapeutic approaches. Our limited understanding of the biological changes that contribute to lymphoma progression is a major obstacle to developing new treatments. To address this critical knowledge gap, we analyzed more than 100 human lymphoma patient samples and normal samples. Our preliminary experiments highlighted a new class of molecules called long non-coding RNAs (lncRNAs) as likely drivers of lymphoma development. These studies will determine the function of the top three lymphoma lncRNAs, and how they contribute to cancer growth and survival. At the completion of these studies, we expect to provide critical insight into lymphoma disease and the potential to discover new therapeutic targets.
Title: The Role of the Histone Demethylase KDM6A in Acute Leukemia
Principal investigator: Lukas Wartman, MD, an assistant professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To characterize how the inactivation of the gene KDM6A can cause specific changes that drive acute myeloid leukemia (AML)
Description: KDM6A is a gene that controls how many other genes are turned on or off, and it is frequently mutated in many types of cancer, including leukemia. KDM6A mutations are thought to cause changes in the expression of other genes that can potentially act as important drivers of leukemia (and cancer in general). In this proposal, we will identify the specific gene expression changes that are associated with the loss of KDM6A activity in leukemia cells and define how these changes are involved in leukemia development. We will also test the ability of drugs that act in the same pathway as KDM6A to treat mouse models of human leukemia. These studies may reveal new approaches for the treatment of leukemia patients, who still usually die from complications of their disease.
Title: Treatment of Metastatic Prostate Cancer with Radioactive PARP Inhibitors
Principal investigator: Buck Rogers, PhD, a professor of radiation oncology, and Dong Zhou, PhD, an instructor in radiology, both at Washington University School of Medicine, and both research members of Siteman Cancer Center
Goal: To determine how a modified FDA-approved agent that targets prostate cancer cells goes about killing the prostate cancer cells and to optimize the amount of drug that is needed to cure mice with prostate tumors
Description: Late-stage prostate cancer is a highly lethal disease with no curative therapeutic options. Recently, the FDA approved a radioactive drug that has increased the survival of late stage prostate cancer patients. This drug is effective even though it is not delivered to the prostate cancer cells themselves, but to normal cells near the prostate cancer. We have developed a drug similar to this FDA-approved agent, but it is targeted to the prostate cancer cells, which should make it much more effective than the FDA-approved agent and with fewer side effects. We have preliminary data from studies involving mice with prostate cancer indicating this approach will work. With this grant, we will determine how our drug kills cancer cells and optimize the amount of drug that is needed to cure mice with prostate tumors. This data are needed to be competitive for NIH funding and other external grants.
Title: Genomics of Acute Myeloid Leukemia
Principal investigator: Timothy Ley, MD, a professor of medicine at Washington University School of Medicine and a research member of Siteman Cancer Center
Goal: To use genome sequencing to fully address why some acute myeloid leukemia (AML) patients do well and others do poorly, as well as study the mechanisms by which some leukemia cells can evade current therapies to cause relapse
Description: AML is a devastating form of blood cancer that most commonly occurs in older patients (average of 67 years); the average survival is less than a year for most older patients. Over the past decade, we and others have used new methods to sequence all of the genes in the leukemia cells of AML patients, and have discovered nearly all of the mutations that can initiate the disease and cause its progression. However, our knowledge base is still incomplete. We still do not fully understand why some patients do well and others do poorly, and we do not fully understand the mechanisms by which some leukemia cells can evade our current therapies to cause relapse. Here, we propose to use more sophisticated sequencing studies to fully address these questions. It should allow us to better define risk at presentation and tailor therapies more precisely for each patient.