Grant: 6548-18 | Translational Research Program (TRP):
Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215
Project Title: Development Of Histone Lysine Demethylase KDM3A Inhibitors For Multiple Myeloma TherapyProject Summary:
Cancer arises from a series of mutations in the DNA sequence that either activate (turn on) genes that allow cells to grow uncontrollably, or silence (turn off) genes that would normally tell a cell to die if it acquires DNA mutations. However, recent evidence suggests that some cancers inappropriately activate or silence genes through a different mechanism, called epigenetics. Epigenetics refers to chemical modifications to DNA and histone proteins that control gene activity without causing mutations in the DNA sequence. Recently, we found that one such epigenetic regulator, KDM3A, is overexpressed in multiple myeloma (MM). Biological investigation into the role of KDM3A in MM reveals that it directly regulates multiple other genes required for cancer cell survival, acting as a master regulator. Knockdown of the KDM3A protein in MM cells induces cell death and reduces tumor size in mouse models of MM. Likewise, knockdown of KDM3A reduces cancer cell interaction with the bone marrow, which is required for MM cell survival. Together, these findings suggest that KDM3A may be a novel therapeutic target for the treatment of MM, a disease that remains incurable.
Here, we propose to develop small molecule inhibitors of KDM3A in order to validate inhibition of KDM3A as a therapeutic opportunity in MM. We have developed an integrated chemical biology approach 1) to chemically synthesize and screen for novel KDM3A inhibitors, 2) to optimize inhibitors for drug activity and selectivity (on target effects) in cells and in animals, and 3) to validate KDM3A as a therapeutic target in cell and animal models of MM. Overall, the goal of this research is to develop small molecule inhibitors of KDM3A and to utilize them to gain a better understanding of how KDM3A drives MM biology, and to fully evaluate the therapeutic potential of KDM3A inhibition in MM. Thus, we have assembled scientists with multi-disciplinary expertise ranged from chemistry, medicinal chemistry, chemical biology and biology to achieve the goal proposed in this research. We envisioned that this research will provide the preclinical rationale to prompt clinical investigation of KDM3A inhibitors for MM which affects ~30,000 new patients a year. The identified small molecule inhibitors developed here will be further optimized for therapeutic use to improve patient outcome in MM.
Grant: R0858-18 | Quest for CURES (QFC):
Location:University of Miami, Atlanta, Georgia 30384-5803
Project Title: The Aging Epigenome: Clues To The Pathogenesis Of MDSProject Summary:
Myelodysplastic syndromes (MDS) are diseases of the blood-producing cells in the bone marrow (BM) with a high risk for progression to an aggressive acute leukemia. While rare before the age of 50, its incidence increases significantly with every decade of age and thus it is likely that age-acquired changes in the BM may predispose to the development of MDS. However, the mechanism behind this increased incidence is not fully understood. We propose that as we age, cells in the bone marrow accumulate changes in the nuclear instructions that govern their behavior. These instructions are encoded not only on their genetic material (known as DNA), but also on a series of chemical modifications of the cell’s genetic material known as epigenetic modifications. These epigenetic modifications are what give cells the ability to “interpret” the information on the genetic code. Therefore, any abnormalities acquired at the epigenetic level can have serious consequences on a cell’s behavior. We hypothesize that cumulative changes in the epigenetic information of BM cells acquired during aging change the cells' behavior and susceptibility to other lesions, laying the foundation for the increased incidence of MDS. We will study the normal changes acquired during aging at both the genetic and epigenetic levels and compare them to the disease-associated patterns seen in MDS in order to identify those epigenetic changes that may predispose for the development of this disorder.
Grant: 3372-18 | Career Development Program (CDP):
Location:The Trustees of Columbia University in the City of New York, Columbia University Medical Center, New York, New York 10027
Project Title: The Role Of Diverse Cytokines Secreted By Myeloid-biased Multipotent Progenitors In Driving LeukemiaProject Summary:
Myelogenous leukemia is a type of blood cancer characterized by the abnormal production of white blood cells in the bone marrow. Abnormally produced white blood cells prevent the proper production of healthy blood cells and eventually lead to failure of the healthy blood system. There are several well-known disease-causing mutations, and many researchers are studying them to find out how the mutations cause disease and to develop treatments based on the targeting of those mutations. However, many cancers are characterized by the accumulation of several mutations, and targeting only one specific mutation is not the most efficient way to treat the disease. Therefore, my study aims to find a treatment that is applicable to a broad range of myelogenous leukemias and is not associated with an individual mutation. In a previous study, we identified a specific immature bone marrow cell population whose expansion is common throughout various myelogenous leukemia mouse models with variant disease-causing mutations. This indicates that expansion of this cell population may reflect the commonalities of the various myelogenous leukemia subgroups and suggests that this cell population is also a critical driver of disease progression in various subgroups. We also discovered ways to experimentally regulate the production of that specific population, which may provide potential therapeutic opportunities. Currently, I study the cellular characteristics of that cell population, with the long-term goal of understanding how expansion of these cells contributes to disease development. More specifically, I will focus on a protein secreted by that population, and I will investigate the function of the secreted protein in driving overproduction of abnormal white blood cells. To achieve my goals, I will use diverse experimental methods using cells isolated from mice as well as several mouse models. My study will provide insight into a mechanism common to the development of various forms of myelogenous leukemia and may contribute to the development broadly applicable therapeutic treatments.
Grant: 5466-18 | Career Development Program (CDP):
Location:The Wistar Institute, Philadelphia, Pennsylvania 19104
Project Title: The Role Of EBNA1 In Epigenetic Regulation Of Gene Expression And EBV LatencyProject Summary:
Epstein-Barr virus (EBV) is a human tumor virus responsible for over 200,000 cancers per year, including multiple blood cancers such as Burkitt’s lymphoma, Hodgkin’s lymphoma, and NK/T cell lymphoma. Like all herpesviruses, EBV can develop a long-term, largely dormant phase called latency, with only occasional reactivation (called the lytic phase). Unlike most other viruses,however, EBV-associated pathogenesis depends on viral latency, rather than an active, lytic infection. During latency, only a handful of viral proteins are expressed, and among these only EBV nuclear antigen (EBNA)-1 is expressed across all forms of EBV-associated cancers. Although it is known that EBNA1 plays a central role in regulating both viral and host gene expression, the mechanisms associated with this regulation remain incompletely understood. Interestingly,epigenetic regulation, or mechanisms of altering gene expression beyond changes to the genetic code, has been shown to play a significant role in cancer development and plays a role in maintaining EBV latency. While EBNA1 is vital in establishing EBV latency and maintaining the latent viral genome, the role that EBNA1 plays in regulating host gene expression and cancer cell development remains unclear. To better understand EBNA1, we will use various approaches to investigate the role of EBNA1 in regulating gene expression on an epigenetic level, where the proteins bound to DNA are modified. We have previously demonstrated that EBNA1 is a direct regulator of genes involved in cell proliferation and survival, and our current studies will expand our knowledge of the mechanism of this regulation and the identification of additional direct targets of EBNA1. A better understanding of EBNA1-mediated gene regulation will give us the opportunity to investigate new mechanisms for inhibiting the function of EBNA1 and validate the potential of EBNA1 as a therapeutic target.
Grant: 3377-18 | Career Development Program (CDP):
Location:Sloan Kettering Institute for Cancer Research, New York, New York 10087
Project Title: Understanding The Effects Of Leukemia-Associated Mutations In Spliceosomal Proteins On Chromatin StateProject Summary:
In the past few years, genetic analysis of leukemias has identified frequent mutations in a class of genes that encodes for proteins participating in a process called RNA splicing. Mutations in RNA splicing factors are now known to be the most common type of mutation in patients with myelodysplastic syndromes (MDS) and related myeloid leukemias as well as chronic lymphocytic leukemia (CLL). These discoveries have resulted in intense efforts to understand how mutations in RNA splicing factors promote the development of leukemia.
RNA splicing is the process whereby genetic information is read from DNA and used to make proteins. Currently, most efforts to study RNA splicing factor mutations have focused on the effects these mutations have on the process of RNA splicing itself. RNA splicing factors, however, are known to play additional roles not directly related to splicing. In accordance with this, we have identified a unique effect of RNA splicing factor mutations on the epigenome. The epigenome refers to chemical changes on chromatin, which are structures in the cell made up of DNA and the proteins surrounding DNA. These chemical changes regulate which genes are expressed from DNA and when they can be turned on and turned off. Based on our preliminary results, we believe that one of the main ways that RNA splicing factor mutations cause leukemia is by altering the epigenome. We have shown that one of the most commonly mutated splicing genes, SF3B1, produces a protein that binds to some parts of chromatin. However, the extent of this binding to different chromatin components and the role that this binding plays in altering the epigenome needs clarification. We are now studying this relationship between RNA splicing factor mutations and the epigenome in more precise detail. Our longer term goal is to utilize this information to develop new therapeutic approaches for leukemia cells carrying RNA splicing factor mutations.
Grant: 2318-18 | Career Development Program (CDP):
Location:Charlotte Mecklenburg Hospital Authority d/b/a Carolinas HealthCare System, Charlotte, North Carolina 28203
Project Title: Optimizing Risk And Response Adaptive Strategies Using Immunotherapy In Multiple MyelomaProject Summary:
Despite the more than three-fold improvement in survival outcomes over the last 15 years, multiple myeloma (MM) remains an incurable disease. There is growing recognition that MM disease biology is complex and that personalized treatment strategies need to be developed for different MM patients. However, the current MM treatment paradigm is largely based on a patient’s eligibility for a stem cell transplant. Thus, an incredibly heterogeneous disease is being treated in a ‘one-size-fits-all’ way that translates into broad variability in patient outcomes. As anti-myeloma therapeutics continue to expand, it is becoming more crucial to personalize treatment approaches to provide the most value to each individual patient. In addition, it is imperative to complement clinical trials with development of prognostic and predictive biomarkers. Prognostic biomarkers provide the likely natural course of MM in an untreated patient, while predictive biomarkers identify the subpopulation of patients who have better outcomes with specific treatment strategies. Over the last decade, researchers have explored new prognostic biomarkers, such as imaging (PET-CT) as well as assays that test for minimal residual disease (MRD), which is the small number of tumor cells that may remain after treatment. However, their utility as predictive biomarkers is not well established. The overarching aim of this proposal is to investigate risk- and response-adaptive clinical trial strategies for newly diagnosed MM while exploring the predictive role of these biomarkers.
We will apply this approach in three clinical trials for newly diagnosed MM. The first two trials compare various combinations of immunotherapeutic agents with current regimens. The first trial examines MRD assays and PET-CT as predictive biomarkers. The second trial assesses MRD to determine the need for transplant and maintenance. The third trial examines the effectiveness of the immunotherapeutic antibody Daratumumab in clearing the bone marrow of residual tumor cells before stem cell collection and transplant in MM patients having a less than ideal response to induction chemotherapy. Together, these studies may provide new therapeutic approaches and improve MRD assessment to better understand a patient’s response. These practice-changing strategies will help move the MM field towards personalized care.
Grant: 6541-18 | Translational Research Program (TRP):
Location:Baylor College of Medicine, Houston, Texas 77030
Project Title: Testing Targeted Therapy In Langerhans Cell HistiocytosisProject Summary:
Rationale and Background: Children with Langerhans cell histiocytosis (LCH) develop destructive lesions that can arise in virtually any organ including bone, brain, liver and bone marrow. LCH occurs with similar frequency as pediatric Hodgkin lymphoma, but there has historically been fewer opportunities for patients with LCH to participate in cancer research studies due to uncertain identity. LCH was first identified over 100 years ago, but only in the past ~5 years has been recognized as a disease in the family of pediatric cancers. Outcomes for children with LCH remain suboptimal, with over 50% failing to be cured with initial chemotherapy, and the majority of patients who are cured suffer long term consequences including problems with growth, control of hormones, and some develop a devastating progressive neurodegenerative condition. Patients who relapse or do not respond to front-line therapy are typically treated with highly toxic chemotherapy or eventually bone marrow transplant. Improved therapies are clearly needed for children with LCH.
Preliminary Studies: In 2010, a mutation in the BRAF gene (called BRAF-V600E), was discovered in over half of LCH tumor samples tested. Over the past 5 years, more mutations in the same cell growth pathway as BRAF (the MAPK pathway) have been discovered, accounting for over 85% of all cases of LCH. In the MAPK pathway, a series of proteins transmit messages from the cell surface to the nucleus of the cell, where that message is translated by turning on or off certain genes. In LCH, this MAPK pathway is overactive and never turns off, resulting in uncontrolled cell growth, resistance to cell death, and formation of destructive LCH lesions. Studies in blood cells from patients with LCH and in mice demonstrated that LCH is caused by activation of the MAPK pathway at specific stages of blood cell development. In early clinical trials with adult patients, LCH lesions responded to vemurafenib, a drug that blocks BRAF-V600E activation. Studies with cells from patients with LCH and experimental mice suggest that blocking MAPK pathway activation with drugs that inhibit MEK activation may be an effective therapeutic strategy for patients with LCH.
Hypothesis and Aims: We proposed to test the hypothesis that cobimetinib, which targets MEK activation, will be a safe and effective treatment for patients with refractory LCH, LCH-neurodegenerative disease, and disorders related to LCH that are also driven by MAPK activation. Additionally, we propose to study the responses associated with certain mutations, determine if cells in blood carrying LCH mutations can be used to follow disease activity, and study new mutations in patients who relapse despite cobimetinib therapy. This study will be carried out through a consortium of LCH disease experts at 11 different institutions through the North American Consortium for Histiocytosis Research.
Grant: 6552-18 | Translational Research Program (TRP):
Location:Walter & Eliza Hall Institute of Medical Research, Parkville 3050, Victoria
Project Title: Long-term In Vivo Imaging Of Bone Marrow Microenvironments In Multiple Myeloma.Project Summary:
White blood cells are soldiers of the immune system. These cells are responsible for surveillance of the body and protection from invading pathogens. When the machinery that controls growth and death of these cells is disrupted by genetic mutations, these cells can undergo massive unregulated expansion. This leads to the development of blood cancers such as leukemia and multiple myeloma (MM).
Blood cancer cells move uncontrolled throughout the body and expand to enormous numbers not normally present in healthy individuals. In addition, the cancer cells can secrete huge amounts of proteins that upset the equilibrium of healthy tissue in the body. In the case of MM, the leukemic cells infiltrate bones. This has dramatic consequences for the health of patients with MM. Cells that normally inhabit the bone are affected by overcrowding caused by expansion of cancer cells. This prevents them from performing their normal daily functions. For example, stem cells responsible for production of red blood cells that circulate throughout the body each day shut down and cannot make more cells leading to shortage of blood. MM cells can also damage the structure of the bones themselves leading to fractures and significant pain in over 80% of MM patients. Currently, this process is poorly understood. Unfortunately, there is no cure for MM and this is at least in part because MM can cells hide in the bone, protected from drugs used as treatment. Thus, considerable effort is needed to develop new treatments to overcome this resistance to treatment and manage the long-term effects of this disease on bone health.
We will solve this problem by watching how MM cells damage bone tissue using cutting edge microcopy. Using 3-dimensional printing technology, we produce custom optical windows that we surgically attach to living bone tissue. Through these optical windows we can view bone tissue for either short periods of time (hours) or throughout the entire disease process (weeks). Therefore, using this technology we will be able to see inside living organisms while MM cells grow, take over and then destroy bone tissue. Using our revolutionary approach, we are able to watch the same cells in the same bone tissue over hours and weeks. This will give us fundamental knowledge about the life cycle of MM and how it responds to treatment that have never been possible before. Once we can directly watch this process in action, we will be able to start to understand how MM cells live, destroy bone and evade therapy. Therefore, we will be able to develop new ways of targeting MM cells so that we can prevent bone damage, and even potentially stop the growth of MM cells leading to a cure.
Grant: 6556-18 | Translational Research Program (TRP):
Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215
Project Title: Interaction Of RUNX1 And The Cohesin Complex In Megakaryocyte Development And Myeloid DiseaseProject Summary:
Inherited mutations in the RUNX1 gene cause abnormal platelets and a predisposition to the development of acute myeloid leukemia. Similarly, patients with RUNX1 mutations that are acquired during adult life have an analogous platelet abnormality and predisposition to acute myeloid leukemia. In order for patients with RUNX1 mutations to progress to acute leukemia, additional mutations need to be acquired. We have found that mutations in the STAG2 gene can cooperate with RUNX1 mutations, likely leading both to the development of worsening platelet abnormalities and progression to overt malignancy.
Our goals are to answer two questions: (1) Does loss of RUNX1 and STAG2 lead to abnormal platelet precursor cell formation, with resultant platelet dysfunction and increased risk of bleeding? If so, we would like to pro-actively identify these patients so that appropriate measures can be taken to mitigate their risk of bleeding, particularly when undergoing diagnostic procedures. (2) Can we model abnormal platelet precursor cell function and AML disease progression in human and mouse bone marrow stem and progenitor cells? If so, this would provide functional evidence that loss of normal function of STAG2 and RUNX1 leads to abnormal platelet precursor cell formation and/or development of leukemia. In addition, these models would facilitate studies of novel therapeutic agents, which are desperately needed for this patient population.
Treatment options for patients with RUNX1 mutations are limited, and better understanding of the mechanisms by which leukemia causing genes contribute to leukemia development in patients will inform the design of urgently needed new treatments. We propose to develop models and investigate therapeutic approaches that have the potential to benefit individuals with RUNX1 mutations.
Grant: R0859-18 | Quest for CURES (QFC):
Location:Joan & Sanford I. Weill Medical College of Cornell University, New York, New York 10022
Project Title: Targeting Of The Senescent Vascular Niche To Treat Age-related Hematopoietic Malignancies.Project Summary:
Physiological aging directly leads to a multitude of age-related diseases, including cardiovascular disease, arthritis and cancer, that affect nearly all systems of the body. The goal of this proposal is to identify alterations in the aged bone marrow vascular system that initiate and facilitate the progression of hematopoietic malignancies. We have demonstrated that vascular cells are a critical component of the bone marrow microenvironment and support the overall health and fitness of blood stem cells. Preliminary data generated in our laboratory demonstrated that the vascular system is altered during the aging process, resulting in the premature aging and a decrease in functionality of the blood stem cells. In order to address whether the aging process promotes hematopoietic malignancies by dysregulating the bone marrow vascular system, we have developed a means to isolate and transplant bone marrow vascular cells to aid in the rejuvenation of the aged bone marrow microenvironment. Utilizing our protocols, we will be able to screen for altered factors produced by aged vascular cells that promote the aggressiveness and elusiveness of leukemic cells. Overall, our laboratory is aiming to design novel therapeutic strategies to be used as an effective means to reduce the morbidity and mortality associated with chemotherapy and radiological regimens used to treat a wide range of aged-related malignancies.