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: 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: 3357-16 | Career Development Program (CDP):
Location:Shanghai Institute of Immunology, , Shanghai
Project Title: VBcl2 Is Essential For Persistent Infection And Pathogenesis Of Kaposi's Sarcoma-associated Herpesvirus (KSHV)Project Summary:
Kaposi’s sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) is associated with the pathogenesis of Kaposi’s sarcoma (KS), body cavity-based lymphoma (BCBL) or pleural effusion lymphoma (PEL), and some cases of Multicentric Castleman’s disease (MCD) and post transplant lymphoproliferative diseases (PTLD). One critical virulence factor involved in KSHV persistence and oncogenicity is the viral homolog of the Bcl2 protein (referred to as vBcl2). Alongside its well-characterized anti-cell death activity, our preliminary studies have established that vBcl2 effectively suppresses the anti-viral autophagy pathway (‘self-eating’, lysosome-dependent degradation and recycling of the intracellular components) by directly targeting the key autophagy effector protein Beclin-1. Based on these, we hypothesize that inhibition of autophagy by vBcl2 constitutes a novel mechanism by which KSHV evades host immunity and confers persistent infection and pathogenesis (Aim 1), and host autophagy limits KSHV persistent infection in humanized mouse model in vivo (Aim 2). Achieving the above aims will define the molecular mechanism by which KSHV vBcl2 regulates host autophagy pathway and KSHV infection. It not only addresses a fundamental biological question, but also can facilitate the development of new preventive and/or therapeutic approaches.
Grant: 4317-16 | Career Development Program (CDP):
Location:Erasmus University Rotterdam, Rotterdam, 3015 GE
Project Title: Targeting Epigenetic Therapy To Specific Acute Myeloid Leukemia (AML) Patient Cohorts For Maximal Clinical EfficacyProject Summary:
With current treatment, acute myeloid leukemia (AML) is fatal for most patients, caused either directly by the disease itself or by complications induced by chemotherapy or stem cell transplantation. Consequently, there is an urgent need for new drugs that are more specific and less toxic. In this project, we will study the efficacy of new classes of drugs, which we call “epigenetic compounds”. These drugs are specifically designed to target abnormalities in patients with leukemia that are not contained in the genetic information of the leukemia cells, but rather in the way the leukemia cells read the information from their genes. Recent work by us and others has shown that such epigenetic therapy holds great promise. However, AML appears to be a very heterogeneous disease, and with current knowledge it is not yet possible to predict which patients benefit from particular compounds. We will directly test these drugs in bone marrow samples obtained from human AML patients. We will test which patients with AML benefit most from treatment with particular drugs. In addition, we will investigate what the mechanism of action of the drugs is. This will allow for the subsequent testing of such drugs in clinical trials, potentially in combination with other compounds.
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.