Grant Finder

LLS investigators are outstanding scientists at the forefront of leukemia, lymphoma and myeloma research at centers throughout the world. Search to see the many research projects that LLS is currently funding.

Grant: 6541-18 | Translational Research Program (TRP):

Location:Baylor College of Medicine, Houston, Texas 77030

Year: 2017

Project Title: Testing Targeted Therapy In Langerhans Cell Histiocytosis

Project 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

Year: 2017

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: 6548-18 | Translational Research Program (TRP):

Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215

Year: 2017

Project Title: Development Of Histone Lysine Demethylase KDM3A Inhibitors For Multiple Myeloma Therapy

Project 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

Year: 2017

Project Title: The Aging Epigenome: Clues To The Pathogenesis Of MDS

Project 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

Year: 2017

Project Title: The Role Of Diverse Cytokines Secreted By Myeloid-biased Multipotent Progenitors In Driving Leukemia

Project 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

Year: 2017

Project Title: The Role Of EBNA1 In Epigenetic Regulation Of Gene Expression And EBV Latency

Project 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

Year: 2017

Project Title: Understanding The Effects Of Leukemia-Associated Mutations In Spliceosomal Proteins On Chromatin State

Project 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: 3370-18 | Career Development Program (CDP):

Location:Boston Children's Hospital, Boston, Massachusetts 02241-4413

Year: 2017

Project Title: Mechanisms Of Orientation-specific RAG Activity In Mediating V(D)J Recombination And Promoting B Cell Lymphoma

Project Summary:

A properly functioning human immune system recognizes disease-causing pathogens via a diverse set of antibodies and T cell receptors (TCRs). These molecules, expressed in a subset of white blood cells termed B and T lymphocytes, can bind pathogens and initiate an immune response. The enormous diversity of antibodies and TCRs is generated by the development of lymphoid cells through a DNA “cut-and-paste” process termed V(D)J recombination. The genes encoding the components of the antibodies and TCRs are diversified by the “cutting” and “pasting” of different segments (V, D, and J). The cutting of these gene segments is executed by an enzyme called RAG. Though DNA breaks are required for normal immune development, they can be improperly joined to other DNA breaks across the genome to create mutagenic events that contribute to the development of cancer. 

Restricting V(D)J recombination to specific chromosomal loops is critical to prevent RAG from escaping and breaking non-intended targets. Genes are contained in larger structures called chromosomes, which are organized within the cell in a series of large chromosomal loops. Chromosome-bound RAG moves directionally, like a train on a track, to locate its target gene cassettes and only stops when it encounters the roadblocks formed by the loop boundaries. We are studying the nature of the engine that moves RAG along the tracks and how normal RAG "tracking" generates diverse antibody repertoires and minimizes potential collateral damage that could lead to blood cancers. We will use genetically engineered cell lines and mouse models to investigate this process. Our research may provide insights into mechanisms that promote normal immune development and the mechanisms that prevent the potent mutagenic activity of RAG, causing unwanted chromosomal lesions underlying some blood cancers. Our over-arching goal is to identify mechanisms and pathways that suppress tumorigenic lesions in developing lymphocytes and to generate information that can potentially serve the development of new therapeutic targets for lymphoid cancers.

Grant: 1347-18 | Career Development Program (CDP):

Location:Sloan Kettering Institute for Cancer Research, New York, New York 10087

Year: 2017

Project Title: Uncovering The Dysregulated RNA Binding Protein Network In Normal And Malignant Hematopoiesis

Project Summary:

Although molecular targeted therapy has dramatically changed how we treat cancer, the treatment for acute myeloid leukemia (AML) remains focused on the use of cytotoxic drugs with many patients eventually relapsing with their disease. One of the major drivers of resistance is the persistence of cells that retain the immature properties of stem cells. Cancer cells are made up of proteins expressed by the genes in the nucleus of the cell. Many RNA molecules comprise the information that is the intermediary between genes and proteins. An emerging focus of study is how these RNA molecules may be involved in disease processes. Our laboratory and others have identified that there are specific RNA binding proteins that regulate gene expression programs that are essential for the survival and immature state of acute myeloid leukemia cells. This network of RNA binding proteins is engaged in the most aggressive leukemias and predicts a poor outcome. We developed a screening strategy to identify other RNA binding proteins that contribute to the leukemic state. Using this novel approach, we identified an RNA binding protein called SYNCRIP that we found to be critical for myeloid leukemia and the response of leukemia patients to therapy. Our studies will further explore SYNCRIP’s role in genetic mouse models,human leukemia cell lines, and primary AML patient samples. We plan to understand the mechanism for the regulation of the dysregulated RNA binding protein network in leukemia and to develop therapeutic strategies for treating this aggressive and devastating disease.

Grant: 6551-18 | Translational Research Program (TRP):

Location:The Board of Regents of the University of Wisconsin System, Madison, Wisconsin 53715-1218

Year: 2017

Project Title: Matrix Remodeling In The Myeloma Niche: Implications For Minimal Residual Disease And Immunotherapy

Project Summary:

Despite a revolution in the way we treat myeloma in the last 10-15 years, the disease remains incurable for the vast majority of patients. We have devised powerful novel agents and strategies that kill myeloma cells efficiently, yet not at 100%. Some residual cells remain even after the best of treatments and act as the “seed” from which the disease relapses and ultimately claims human lives. In the last 4-5 years, we have become much better at measuring this “minimal residual disease”. Ultimately however, we should not only recognize and size the enemy, we should eliminate it. The burning question therefore becomes: how are these remaining cells protected and shielded from harm? What is the best way to go after them?

We believe that the best strategy against residual myeloma cells is to mobilize the immune system to attack them. This is called “immunotherapy”. Immunotherapy can be a powerful weapon against cancers because it is endowed with inherent specificity and “memory” (in a manner illustrated by how vaccines work): once the immune system recognizes the tumor as foreign and undesirable, it can keep it in check for long time- hopefully, for ever. However, only a small number of patients have so far benefited from cutting-edge immunotherapies that have seen the front page of the New York Times. Part of the reason is that tumors are very capable at putting up bulwarks that fend off the immune system’s “killer” cells. New immunotherapies, such as drugs called “checkpoint inhibitors” work to remove the “brakes” from the immune killer cells. Still, they do not work for all patients. 
Our approach is to “breach the bulwarks” that tumors put up to ward off the immune-killer cells. Once the defenses are gone, immunotherapy-mobilized killer cells have a better chance to work. We recently found that a component of the bone marrow environment in which myeloma cells and immune cells interact with each other is a “double-agent”. The “double-agent” is a bone marrow matrix component called versican. In its intact form, versican helps the myeloma tumor cells by neutering the immune system. However, in many cases, a bit from versican’s end (called “versikine”) gets broken off by specialized enzymes, called ADAMTS proteases. Versikine then stimulates the immune system to fight myeloma cancer cells. In other words, versikine (the “daughter” molecule) antagonizes versican (the “mother” molecule). The current proposal aims to investigate the role of versican and versikine in mobilizing the immune system to attack myeloma cells. Tipping the versican-versikine balance may provide powerful marching orders to anti-myeloma immune fighter cells.