Grant: 9001-16 | Transforming CURES Initiative (TCI):
Location:Northwestern University, Evanston, Illinois 60208
Project Title: Identification Of Pathways That Promote Transformation Of The MPNs To AMLProject Summary:
Grant: 6483-16 | Translational Research Program (TRP):
Location:St. Jude Children's Research Hospital, Memphis, Tennessee 38148-0949
Project Title: Engager-T Cells For The Adoptive Immunotherapy For AMLProject Summary:
Acute myeloid leukemia (AML) is a type of blood cancer that is in need of new therapies, as patient suffering from high risk disease have little chance of cure. Aggressive treatment with traditional chemotherapy drugs can lead to complications and severe toxicities. Using the patient's own immune system to fight cancers is one promising approach to improve outcomes for AML patients, who do not benefit from current therapies. However, the body’s immune defenses against cancers often fail because the cancers do not induce or actively inhibit immunity. Cancer treatments consisting of the infusion of T cells (one component of the patient’s own immune system) that recognize parts of tumors have shown promise in early clinical studies. We have developed a new strategy to produce AML-specific T cells with a genetic approach that redirects not only the genetically modified cells, but also unmodified T cells to AML cells. Studies in our laboratory have shown good activity of our AML-specific T cells against leukemia in preclinical models that closely mimic human disease. In this grant we are now planning to build on our encouraging results. We are proposing to introduce a ‘safety switch’ into our AML-specific T cells for use in humans, develop clinical grade reagents and obtain all regulatory approvals to conduct a clinical study. Thus, at the end of grant we expect to have everything in place to conduct a clinical study to test the anti-leukemia activity of our T cells in patients with AML for which we will seek separate funding.
Grant: 6492-16 | Translational Research Program (TRP):
Location:Duke University Medical Center, Durham, North Carolina 27708
Project Title: Novel Combinations To Overcome Resistance To Histone Deacetylase Inhibitors In LymphomaProject Summary:
Histone deacetylase inhibitors are effective in the treatment of some lymphomas, but resistance to therapy almost always develops and limits their effectiveness. In this proposal we investigate new methods to overcome resistance by identifying new combinations of drugs.
Grant: 1334-16 | Career Development Program (CDP):
Location:Cincinnati Children's Hospital Medical Center, Cincinatti, Ohio 45229
Project Title: Investigating Genetic And Molecular Determinants Of Myelodysplastic SyndromesProject Summary:
Myelodysplastic syndromes (MDS) are malignant diseases of the bone marrow as a result of defective blood-forming cells, otherwise known as hematopoietic stem cells (HSC). For many genes implicated in MDS, it is not known how they contribute to HSC defects, abnormal blood production, and AML, and this gap in knowledge impedes development of novel therapeutics. Population-based studies revealed that chronic immune stimulation increases the risk for MDS. The relevance of the immune pathway to MDS is further supported by studies showing that genes of this pathway are abnormally expressed in MDS. One recurring example is TRAF6, which is overexpressed in MDS HSC. Mice were engineered to mimic MDS HSC with elevated levels of TRAF6. From preliminary data, TRAF6 overexpression in mouse HSC recapitulates aspects of human MDS, making it a valuable resource to understand the pathogenesis of MDS. In this proposal, we will investigate a novel mechanism that contributes to HSC dysfunction in MDS conferred by TRAF6-mediated alterations in mRNA splicing. Our proposal is significant because it connects two common genetic alterations in MDS: chronic immune pathway activation and altered mRNA splicing. This molecular connection, not only has implications in MDS, but also in normal HSC function and host defense mechanisms. We anticipate that the proposed research will advance our knowledge about the molecular and cellular basis of MDS, and reveal novel treatment strategies.
Grant: 1335-16 | Career Development Program (CDP):
Location:Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724
Project Title: Targeting The Chromatin Reader Protein TRIM33 As Epigenetic Therapy In B Cell NeoplasmsProject Summary:
The central therapeutic objective for lymphoid malignancies is the development of chemotherapy-free drug regimens than can effectively eradicate cancer cells with minimal collateral cytotoxicity. Biological agents that selectively eliminate normal and malignant B cells (e.g. anti-CD20 antibodies) or small-molecules that inhibit B lymphocyte intracellular signaling (e.g. PI3Kδ and BTK inhibitors) are well-tolerated in humans and have established efficacy in mature B cell neoplasms. However, acquired resistance limits the clinical benefit of such agents, implying that combination regimens will be essential to achieve long-term disease control. I seek support for research that develops the chromatin reader protein TRIM33 as a next-generation epigenetic drug target in B cell malignancies. Our preliminary data provide strong evidence for the selective dependence of normal and malignant B cells on TRIM33. Now we seek to translate these findings into pre-clinical development by performing critical mechanistic experiments in appropriate biological systems while simultaneously developing chemical probes that modulate TRIM33 function in cells. Based on complementary expertise and the success of prior research, the Vakoc laboratory is strongly positioned to validate TRIM33-inhibition as a therapeutic modality in cancer and determine the suitability of this approach for downstream clinical development.
Grant: 5448-16 | Career Development Program (CDP):
Location:The Johns Hopkins University School of Medicine, Chicago, Illinois 60693
Project Title: Identification Of Factors Required For Dysregulated Signaling To NF-kappaB In Diffuse Large B Cell LymphomaProject Summary:
A key arm of the human immune system consists of B cells, white blood cells that sense the presence of an infection, secrete antibodies, and help recruit other cells in the immune system to help fight the infection. Several types of human lymphoma develop as a result of mutations that dysregulate the molecular machinery responsible for normal B cell function. Often in lymphoma, the dysregulated machinery makes the B cell grow and divide out of control, as if the cell is receiving a signal that an infection needs to be challenged. Our group has been studying this signaling machinery, trying to identify the component parts, figure out how they operate normally, and how mutations in human lymphoma disturb the machinery and cause disease. We have recently developed a new approach aimed at identifying previously undiscovered parts of this machinery. In this application, we propose to apply our new strategy to screen all genes for a role in the signaling that is dysregulated in a type of lymphoma called Diffuse Large B cell Lymphoma (DLBCL), the most common type of Non-Hodgkin lymphoma. Any genes that emerge in our approach will then be validated to prove that they are critical players in lymphoma cell growth or in normal B cell function. It is our hope that our results will a) help explain how DLBCL develops in patients, b) provide new molecular strategies for DLBCL diagnosis, and c) provide new targets for novel therapeutics designed to treat patients with DLBCL.
Grant: 9004-16 | Transforming CURES Initiative (TCI):
Location:Boston Children's Hospital, Boston, Massachusetts 02241-4413
Project Title: Modeling MDS And Leukemia Predisposition For Novel Therapeutics.Project Summary:
Monosomy 7 refers to deletions of chromosome 7 or deletion of a specific region of chromosome 7 (7q). Monosomy 7 is associated with poor survival using standard chemotherapy treatments. Monosomy 7 is a common characteristic of MDS/AML arising in patients who were previously treated with chemotherapy for other malignancies or in patients with a genetic predisposition to cancer. The paucity of model systems to study monosomy 7 has impeded the development of new therapies for this devastating disorder. Current evidence indicates that additional genetic mutations are required for monosomy 7 to progress to leukemia. Therefore, we developed induced pluripotent stem cells (iPSC) from patients with a leukemia predisposition syndrome, Shwachman-Diamond syndrome (SDS), and introduced a deletion of 7q. Monosomy 7 in SDS patients is associated with a high risk of progression to leukemia. The advantage of iPSC is that they can develop into blood cells. Since we already have these cells in hand, we are poised to investigate the effect of monosomy 7 on blood cell production and identify monosomy 7-associated molecular alterations to understand how monosomy 7 promotes leukemia. We will also treat iPSC with different agents to find treatments that preferentially eradicate monosomy 7 cells relative to control non-monosomy 7 cells. Promising agents will be further tested on monosomy 7 MDS/AML bone marrow samples from non-SDS patients. Our aim is to develop new treatment strategies.
Grant: 6498-16 | Translational Research Program (TRP):
Location:Vrije Universiteit Brussel, Brussels, 1090
Project Title: Immunotherapy Targeting Neo-epitopes In Multiple MyelomaProject Summary:
Multiple myeloma (MM) is caused by the proliferation of malignant monoclonal plasma cells in the bone marrow. It is the second most frequent neoplasm of the blood and bone marrow. Since the introduction of new drugs and the availability of stem-cell therapy, the survival rate of MM patients has increased faster than that of any form of cancer. However, due to the occurrence of drug resistance, MM remains incurable. Therefore, there is a need for novel therapies.
The aim of this project is to introduce a new immunotherapy for multiple myeloma. Immunotherapy is a relatively new treatment modality for cancer patients and is based on the observation that tumor cells express “tumor associated antigens”, which can be recognized by the T lymphocytes of the patients. Activated T cells that recognize a tumor-associated antigen on a tumor cell have the capacity to kill this tumor cell (“killer T cells”).
It is well known that the genetic information present in cancer cells contains many mutations: the genetic code of cancer cells differs from the genetic code of healthy cells from the same patient. Some of these mutated genes can encode for antigens (“neo-antigens”), which are thus specifically expressed on cancer cells, but not on healthy cells. These neo-antigens are patient-specific as the mutations that occur in cancer cells differ between patients. It would be of particular interest to stimulate T cells that recognize neo-antigens expressed by myeloma cells through immunotherapy.
In our project, we will isolate tumor cells from multiple myeloma patients and examine the genetic code of the tumor cells for the presence of mutations that could result in the expression of neo-antigens. We will evaluate the feasibility to raise T cell responses specific for the identified neo-antigens. If our results are promising, we will offer the opportunity to myeloma patients to participate in a clinical trial where we will provide a personalized vaccine developed to specifically enhance immune responses directed against the neo-epitopes expressed by the myeloma cells.
Grant: 6497-16 | Translational Research Program (TRP):
Location:Duke University Medical Center, Durham, North Carolina 27708
Project Title: The Notch2-BCR Axis: Targeting Drivers Of B Cell Fate In Chronic GVHDProject Summary:
An estimated 60-80% of long-term survivors of HCT will develop chronic graft versus host disease (cGVHD), and death results in up to one third of the long-term post-HCT survivors. Treatments and prevention strategies for cGVHD are urgently needed. Chronic GVHD is clinically akin to acquired autoimmune diseases, representing unacceptable toxicity for patients who are otherwise cured of their cancer. By studying primary patient samples, our laboratory has identified cell signaling pathways that are hyper-activated in particular types of cGVHD patient cells. These immune cells, called B cells, represent particularly interesting therapeutic targets because they are known to contribute to cGVHD pathology in relevant murine models of this disease, and importantly, elimination of B cells in patients with anti-CD20 antibody, rituximab, does not result in cancer relapse after HCT. Studies in our lab have uncovered the mechanisms behind the limitation of global B cell depletion with rituximab. We found that factors present in the post-transplant setting prime aberrant B cells for activation and survival. While we and others are currently pursuing development of small molecule inhibitors of signaling pathways important for B cell survival and activation, we are finding that these inhibitors also target other cells. The lack of specificity for cGVHD B cells of these agents will potentially result in unwanted toxicity or in tumor relapse. We have therefore continued to pursue other molecular pathways that potentially drive pathological B cell production but that do not affect other organ systems. Very recently, we have discovered the importance of a pathway that warrants further study. This pathway, called the Notch2 pathway, is known to be critical for development of certain B cell subsets that we have identified in patients with cGVHD. We now have preliminary data showing that cell surface Notch2 expression on cGVHD B cells is increased. Cell surface Notch2 represents a viable therapeutic target of a novel monoclonal antibody available to our group for further study. Published and preliminary data as well as the availability of a novel therapeutic agent position my group, along with expert collaborators, to examine the Notch2 B cell signaling pathways in primary cells from HCT patients and using a murine model of cGVHD. Despite years of research, chronic graft versus host disease (cGVHD) remains common, debilitating and deadly. Our immediate goal herein is to develop a novel targeted agent for patients undergoing HCT hypothesizing that we will abrogate clinically significant cGVHD while maintaining anti-tumor responses.
Grant: 3356-16 | Career Development Program (CDP):
Location:Sloan Kettering Institute for Cancer Research, New York, New York 10087
Project Title: Investigating Physiologic L-2-hydroxyglutarate Production And Its Relevance To Normal Hematopoiesis And LeukemogenesisProject Summary:
Leukemia-associated mutations in the enzymes isocitrate dehydrogenase 1 and 2 result in production of the ‘oncometabolite’ D-2-hydroxyglutarate (D-2HG), which poisons machinery required for normal gene expression and locks leukemia cells in an immature stem cell-like state. 2HG is a chiral molecule that can exist in mirror-image D- or L- conformations, but biologic sources and activities of L-2HG remain poorly understood. We discovered that under conditions of oxygen limitation (a.k.a. hypoxia), cells potently and selectively produce L-2HG via a novel metabolic pathway. Hypoxia-induced L-2HG inhibits gene expression machinery and promotes stem cell-like marks. Normal blood stem cells and leukemia stem cells reside in hypoxic regions of the bone marrow. Thus, we hypothesize that L-2HG might represent a molecular mechanism whereby the hypoxic niche promotes and maintains the immature state of normal blood stem cells and leukemia stem cells. To test this hypothesis, we propose the following aims: (1) use cell culture systems to more fully elucidate the effects of L-2HG on gene expression machinery, (2) employ mouse models to determine if L-2HG influences the development of normal blood cells or leukemia, (3) utilize patient samples to investigate a potential role of L-2HG in human leukemia. Investigating the role of L-2HG in normal blood cells and leukemia will help build a scientific framework to aid development of novel anti-cancer therapeutics that target metabolic enzymes.