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.
Grant: 5460-18 | Career Development Program (CDP):
Location:Sloan Kettering Institute for Cancer Research, New York, New York 10087
Project Title: Defining The Molecular Determinants Of Cysteine Acquisition And Redox Homeostasis In B Cell LymphomaProject Summary:
A key feature of blood cancer cells is the adaptation of their internal cellular metabolism to support nutrient utilization for continuous cell proliferation. Excessive nutrient consumption results in increased levels of reactive oxygen species (ROS). Since increased ROS levels are toxic, there must be countermeasures in place in order for the tumor cell to survive. It is therefore critical for these cancer cells to increase antioxidant capacity in order to overcome the oxidative stress caused by ROS during cancer progression. My research is designed to provide novel insights into the metabolic basis of how cancer cells regulate oxidative stress to maintain an appropriate equilibrium for their own survival. This process of maintaining equilibrium is called “redox homeostasis.”
My preliminary results suggest that two mechanisms function to maintain redox balance in cancer cells and that most cancer cells are committed to one or the other mechanism. It is thought that many blood cancer cells preferentially depend only on the mechanism that creates the amino acid cysteine by modifying another amino acid, which then is converted into the ROS scavenger glutathione. My research will employ metabolic analysis and biochemical approaches to investigate the molecular basis of redox controls and apply various cellular assays to evaluate the functional significance of these controls. My research may reveal critical knowledge of how blood cancer cells maintain redox homeostasis and may also contribute to advances in the clinical treatment of these cancers. Pharmacological inhibitors are currently available to target the metabolic pathway that supports redox balance in blood cancer cells. These chemicals may be adapted and tested for clinical use. Furthermore, the proposed mechanism reveals the metabolic vulnerability of these cancer cells. Therefore, a specific diet may be applied clinically, alone or in combination with standard chemotherapeutics, which may lead to better outcomes for some blood cancer patients.
Grant: 5472-18 | Career Development Program (CDP):
Location:British Columbia Cancer Agency Branch, Vancouver, British Columbia V5Z 1L3
Project Title: Roles Of MicroRNA MiR-146a In Hematopoietic Stem Cell FunctionProject Summary:
Myelodysplastic syndrome (MDS) is a cancer of blood stem cells, the blood-forming cells in the bone marrow. In MDS, cancerous blood stem cells lose the ability to make blood cells, and can also block the function of the remaining normal blood cells. Aging and environmental factors are associated with developing MDS, but how these processes affect the function of both cancerous and coexisting normal blood stem cells in MDS remains poorly understood. Few treatments are available for MDS, and treatment resistance develops in most patients; therefore, understanding the molecular mechanisms that disrupt blood stem cell function in MDS is critical for improving patient outcomes.
I aim to study the molecular mechanisms affecting the function of coexisting cancerous and normal blood stem cells in a mouse model of MDS. I will focus in particular on a subtype of MDS that lacks the gene miR-146a, as we have found that miR-146a deletion in a mouse model causes aggressive MDS symptoms with severe defects in blood stem cell function. To better recreate the bone marrow of MDS patients in which normal and mutant cells coexist, I will co-transplant equal amounts of normal bone marrow with miR-146a-deleted bone marrow, and study the function of both cancerous (miR-146a deleted) and normal (miR-146a intact) blood stem cells. Our data suggest that miR-146a deletion activates inflammation, increases cellular aging, and disrupts energy metabolism in blood stem cells. I will use chemical and genetic strategies to manipulate inflammation, aging pathways, and energy metabolism, with the hope of reversing the dysfunctions of cancerous and normal blood stem cells in this mouse model.
This research will provide the first evidence as to whether drugs targeting inflammation, aging pathways, or energy metabolism may be useful additions to current treatment regimens for MDS. As few effective long-term treatments are available for MDS, my research may one day improve the prognosis for patients with MDS.
Grant: 2317-18 | Career Development Program (CDP):
Location:Washington University in St. Louis, St. Louis , Missouri 63130
Project Title: Targeting Leukemia Stromal Interactions In T-ALLProject Summary:
T-cell acute lymphoblastic leukemia (T-ALL) is a subtype which comprises about 20% of all cases of acute lymphoblastic leukemia. T-ALL is a particularly rare disease in adults, with only about 600 new cases per year in the United States. Furthermore, the prognosis of adults is poor; only 40% of adults with T-ALL are cured with current treatments.
Our laboratory work has demonstrated that T-ALL cells interact with normal cells present in their local environment (called the “microenvironment”), which provides key signals that regulate tumor growth and survival. Our research has focused on a specific protein, CXCR4, which is present in T-ALL cells. In T-ALL, the tumor microenvironment provides a potent growth and survival signal, which is mediated by CXCR4, to T-ALL.
We hypothesize that it is possible to disrupt this tumor-microenvironmental interaction as a means to treat T-ALL patients. We will disrupt the key survival signal to T-ALL cells using a novel inhibitor of CXCR4 known as BL-8040. We are currently conducting a multicenter study to combine BL-8040 treatment with chemotherapy in patients with T-ALL that has relapsed or is refractory to standard treatments. As part of this study, we will test blood and bone marrow samples from patients after treatment to determine the effects of BL-8040 on leukemia cells. We will also conduct additional preclinical studies to test the effects of new combinations of drugs to improve the effectiveness of BL-8040. The overall goal of this project is to target tumor-microenvironment interactions to improve the outcomes of patients with T-ALL.
Grant: 5464-18 | Career Development Program (CDP):
Location:Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037
Project Title: The Impact Of Immunoglobulin Isotype (IgM Vs IgG) On B Cell Lymphomagenesis And Progression.Project Summary:
B-cell lymphomas continuously multiply because growth regulation signaling is altered to stay ‘on’ all the time. This signaling is normally triggered by activation of proteins called receptors on the cell surface. Most lymphomas require signaling from a group of receptors called the B-cell receptor (BCR). Normal B-cells produce a type of BCR, called immunoglobulin (Ig), in a process called the germinal center (GC) reaction. There are several types of Ig subtypes – IgM, IgG, and IgA isotypes—which are produced during the GC in response to stimuli generated by agents foreign to the body. B-cells with different Ig isotypes behave and function differently. Diffuse large B-cell Lymphoma (DLBCL) frequently arises during the GC reaction and express either IgM, IgG or IgA types of BCR. However, the signaling potential and role of Ig isotypes in B-cell lymphoma is poorly understood.
DLBCL can be further sub-categorized into two subgroups: the Germinal Center B-cell type (GCB) DLBCL and Activated B-cell type (ABC) DLBCL. While ABC-DLBCL is a more aggressive disease with a poorer clinical outcome, the GCB-DLBCL is a less aggressive disease with better patient outcomes. Importantly, both subgroups of DLBCL depend on B-cell receptor (BCR) signaling for their survival and proliferation. Interestingly, GCB-DLBCL cells primarily express the IgG isotype of BCR, whereas the majority of ABC-DLBCL cells express IgM. Consistent with these findings, the two subgroups of DLBCL respond differently to BCR signaling inhibition by ibrutinib. In a recent study, there was only a 5% response rate among GCB-DLBCL patients treated with ibrutinib, whereas there was a 38% response rate among ABC-DLBCL patients. These findings, along with the expression of different Ig isotypes, are suggestive of the involvement of differential BCR signaling cascades in the pathogenesis of GCB- versus ABC-DLBCL. To address this idea, we analyzed changes in protein activation between IgM and IgG positive cells in normal B-cells from mice. Remarkably, we observed differential activation of common signaling components among the different Ig isotypes. We are currently seeking to elucidate the molecular mechanisms by which different Ig isotypes impact the survival and proliferation of lymphoma cells. We will also study the effect that these differences may have on regulating the sensitivity of lymphoma cells to approved therapies. Lastly, during these studies we hope to uncover novel therapeutic targets, which may eventually lead to better treatments for DLBCL.
Grant: 1352-18 | Career Development Program (CDP):
Location:New York University School of Medicine, Boston, Massachusetts 02241-415026
Project Title: MicroRNA Regulation Of Leukemia Stem CellsProject Summary:
Acute myeloid leukemia (AML) is composed of two populations of cells with differing characteristics. The bulk population directly gives rise to the disease symptoms. The second population is very small and is composed of leukemia stem cells (LSCs), whose role is to initiate disease and generate the AML bulk population. These self-renewing LSCs are therapy resistant and mediate disease relapse; therefore, it is critical to understand the mechanisms that regulate LSCs in order to develop strategies designed with the intent to cure.
The characteristics of all cells are determined by DNA contained in the nucleus of the cell. The information DNA provides is converted to RNA, which is exported out of the nucleus into the cytoplasm of the cell, where the cell’s proteins are produced. Small RNA molecules, called microRNAs (miRNAs) regulate the expression of protein-encoding genes in cells.
My laboratory has shown that miRNAs can regulate normal blood stem cell function, promote the development of AML, and regulate LSCs. We have shown that two nearly identical microRNAs are frequently overexpressed in LSCs, but it is unclear what their relative contributions are to regulating leukemia cell survival and LSC function. We hypothesize that these two microRNAs can serve overlapping but non-redundant functions due to differences in their location within the cell. Indeed, while most miRNAs are thought to function in the cytoplasm of the cell, some microRNAs enter the nucleus, and we predict that such a nuclear distribution will affect their ability to regulate genes critical for LSC function. Leveraging our expertise in LSC biology, as well as novel technologies that we have either developed or optimized, we seek to better understand the role of these critical miRNAs in AML disease initiation and maintenance. Thus, we propose to: 1) Determine whether structurally similar microRNAs play similar or unique roles in LSCs; 2) Determine whether the subcellular location of microRNAs dictates their ability to regulate LSC function; and 3) Identify the genes that these microRNAs regulate, specifically in LSCs. Overall, we expect to not only reveal how microRNAs regulate LSCs but also to provide general insights into how microRNAs can differentially regulate gene expression based on their position within a cell. These investigations may lead to a better understanding of AML and may provide avenues for novel therapeutic approaches.
Grant: 6543-18 | Translational Research Program (TRP):
Location:Children's Research Institute, Washington, District of Columbia 20010
Project Title: Novel Combination Immunotherapies For High Risk Hodgkin's LymphomaProject Summary:
Hodgkin’s lymphoma (HL), a type of blood cancer is largely curable but with significant long-term side effects. Moreover 10-20% of patients are resistant to treatment and difficult to cure. HL is unique that the tumor cells are surrounded by an inhibitory environment that makes the immune system dysfunctional and allows evasion from an effective anti-tumor response. Understanding this environment may provide insight into how we can spur the immune system to attack HL cells effectively. Like many cancer cells, HL cells escape the immune attack by expressing a protein called PD1 or PDL-1, which is is normally expressed by healthy T cells to prevent them from attacking healthy cells. PD1-inhbitors are drugs that can bind to the PD-1/PDL-1 on lymphoma cells thereby releasing the “brakes” on the immune system to mount a strong attack on the HL cells. The lymphoma cells also secrete certain chemicals like TGFβ which incapacitates the immune cells to kill the lymphoma cells effectively. The goal of this project is to understand how we can change the tumor microenvironment sufficiently to unleash pre-existing anti-tumor immune responses and allow more successful incorporation of killer- T cells. We will determine if PD1 inhibitors when given in combination with the administration of a novel cancer killing T-cell therapy will produce long-lasting cures in patients with high risk HL with less side effects than conventional chemotherapy. Finally, we will continue to improve the efficacy of our combination immunotherapy approach by also engineering the cancer killing T cells to become resistant to the inhibitory chemical TGFβ which is released by the HL tumor cells and has devastating effects on T cell function in vivo. In the laboratory we will determine if these engineered T cells have enhanced killing ability compared to the non engineered T cells.
Grant: 6537-18 | Translational Research Program (TRP):
Location:Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Project Title: Attenuating Oncogenic Myc-driven Transcription Via Modulation Of The Max Heterodimer PartnerProject Summary:
An emerging therapeutic strategy involves controlling the function of overactive transcription factors that regulate the expression of established disease genes in cancer. As transcription factors have historically proven recalcitrant to drug discovery, several labs are pursuing this opportunity by developing indirect inhibitors of transcription that target various chromatin binding factors as well as kinases that play a role in transcriptional initiation. Our lab is focused on discovering and developing small molecules that perturb the function of oncogenic transcription factors by targeting the protein itself or close interacting partners in relevant complexes. We use unbiased binding assays involving small-molecule microrrays to search for compounds that bind to either purified transcription factor, presumably in a highly disordered state, or to protein complexes containing the transcription factor from cell lysates corresponding to various tumors of origin. While our lab is using this approach to identify chemical probes for several transcription factors, roughly half of our group is focused on developing targeted strategies to modulate MYC-driven transcriptional programs. Activation of MYC is one of the most frequent oncogenic events in human malignancies and inactivation of MYC using small molecules may provide a general and effective approach to treating cancer, as MYC is one of the most common drivers of malignancy. Using our screening approach, we identified compounds that bind to c-MYC or its interacting partners such as MAX and found a subset of compounds that modulate a variety of MYC functions in cells, including MYC-mediated transcription. This preliminary data forms the foundation of the studies proposed herein that emphasize advancing the compounds to develop bona fide chemical probes by precisely characterizing their molecular and cellular mechanisms of action as well as synthetically optimizing the compounds with emphasis on improving physicochemical characteristics. Moreover, we propose translational studies involving a lead compound that preliminarily impacts tumor volume in an aggressive murine model of MYC-driven lymphoma. Pursuant to these aims, our lab is comprised of a collaborative, multi-disciplinary team with expertise in methods related to transcriptional profiling, chromatin profiling, quantitative proteomics, computational biology, synthetic chemistry, molecular recognition, and pharmacology. Through these efforts, we hope to build a toolbox of chemical probes that modulate MYC function via different molecular mechanisms and to evaluate these mechanisms as candidates for therapeutic intervention. A key goal for our lab is to make chemical probes and structurally related inactive analogs for MYC and other transcription factors available to the wider research community without encumbrance.
Grant: 6546-18 | Translational Research Program (TRP):
Location:Boston Children's Hospital, Boston, Massachusetts 02241-4413
Project Title: Deciphering Epigenetic Cross-talk In Diffuse Large B-cell LymphomaProject Summary:
With an estimated 73,000 new cases of non-Hodgkin lymphoma (NHL) and 20,000 deaths in the year 2016 alone from NHL, novel therapeutic strategies are urgently required. Specifically, the diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL, and contributes about 30% of new NHL diagnosis every year. Our interest in blood biology, and its mis-regulation is several blood disorders including blood cancers, led us to investigate the role of chemical modifications on one of the most fundamental proteins of like- the histone proteins. We investigated if various histone modifications would be critical for the survival of DLBCL cells. Interestingly, we discovered a unique chemical that specifically abrogates the survival of DLBCL cells but not of any other type of blood cancer cells. We have found that cells commit ‘suicide’ after treatment with our chemical, using a very specific pathway. Furthermore, we have identified a key protein responsible for gene regulation as a likely target of our chemical. This novel target is highly expressed in DLBCL patients, who fare worse after the standard-of-care therapy for DLBCL. Additionally, by performing high throughput gene expression studies, we have identified a completely unique mechanism that bypasses three very frequent mutations found in DLBCL patients, and also explains why our chemical is not very effective against cells that are not coming from DLBCL patients. In essence, we have identified a histone modification pathway that when manipulated kills multiple types of DLBCL cells, but not other types of hematological cancers. We will employ cutting-edge molecular and cell biology, biochemistry, and mouse genetics to carry out specific aims that will a) establish the novel mechanism that allows DLBCL cells to survive. b) Establishes our chemical as a potent strategy against DLBCL through experiments conducted in mouse and c) reveal new details about how histone modifications regulate the formation, and development of B and T cells in humans.