Grant: 8012-18 | Screen to Lead Program (SLP):
Location:H. Lee Moffitt Cancer Center & Research Institute, Atlanta, Georgia 30374-2801
Project Title: Rationally Designed Dual BRD4-Kinase Inhibitors For The Treatment Of Myeloid CancerProject Summary:
Current anti-cancer targeted drugs often fail due to ineffectiveness or drug resistance, suggesting alternative strategies are needed to develop effective therapies. We recently determined that certain drugs bind to and inhibit two different classes of proteins that play important roles in cancer. These two classes are called kinases and BET proteins, which have completely different functions in the cell. The general approach in drug discovery has been to optimize a single drug to target a single protein.
Grant: 5470-18 | Career Development Program (CDP):
Location:Leland Stanford Junior University, San Francisco, California 94144-4253
Project Title: Dissecting The Topological Consequences Of Mutations In The Cohesin Complex And Their Contribution To Human Leukemia Initiation And Progression.Project Summary:
The human genome is exquisitely organized, packing five feet of DNA into a microscopic nucleus. This level of compaction requires an equally impressive level of organization. Not only does the DNA have to fit into such a tiny space; the genes required for the cell’s function must be properly expressed with high fidelity. To accomplish this seemingly insurmountable task, the genome is organized into a cascading series of loops whose formation is mediated by a multi-protein complex called the cohesin complex.
Grant: 5471-18 | Career Development Program (CDP):
Location:Harvard Medical School, Boston, Massachusetts 02241-5649
Project Title: Studying The Function Of Co-activator MAML1 In Notch-associated T-cell Acute Lymphoblastic LeukemiaProject Summary:
Normal cell growth and differentiation relies on a small number of signaling pathways that direct the gene expression patterns unique to each cell type. One pathway particularly important in cell-cell communication is the Notch pathway, which normally relies on direct contact between a signal-sending cell and a signal-receiving cell. After the signal is activated, a portion of the Notch protein enters the cell nucleus and forms a complex with two other proteins, called RBPJ and MAML1, to regulate the expression of genes that control cell growth and cell fate decisions.
Grant: 1348-18 | Career Development Program (CDP):
Location:Northwestern University, Evanston, Illinois 60208
Project Title: The Role Of Plek2 In The Pathogenesis Of Myeloproliferative NeoplasmsProject Summary:
Myeloproliferative neoplasms (MPNs) are a group of bone marrow diseases with overproduction of mature blood cells and increased risk of evolving to acute leukemia. A specific mutation on one of the blood cell surface proteins called Jak2 is the leading cause of this group of diseases. The discovery of this mutation led to the development of inhibitors specifically targeting Jak2. However, these inhibitors are not curative.
Grant: 3375-18 | Career Development Program (CDP):
Location:Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024
Project Title: Enhancing Adoptive Immunotherapy Of AML With Engineered T Cells By Expressing Immunomodulatory Fusion Proteins That Overcome Inhibitory SignalsProject Summary:
Acute myeloid leukemia (AML) is the most common acute leukemia in adults and has the worst survival rate of all leukemias, with only 26% of AML patients surviving 5 years. Since our immune cells can have the ability to eradicate tumors, immunotherapeutic approaches are being developed as treatment options with the goals of providing better efficacy and fewer side effects.
Grant: 7014-17 | Specialized Center of Research Program (SCOR):
Location:Memorial Sloan Kettering Cancer Center, New York, New York 10087
Project Title: Novel Immune Therapy Of LymphomaProject Summary:
Patients with relapsed diffuse large B cell lymphoma (DLBCL) have limited curative options, once their tumor fails to respond to standard chemotherapy regimens. Our group and others have recently demonstrated that activating the patients’ own immune cells can induce clinical responses, even in chemotherapy-refractory DLBCL patients. The central goal of this SCOR is to establish a collaborative team-science approach aiming at the development of new immune therapeutic strategies for DLBCL.
Grant: 3374-18 | Career Development Program (CDP):
Location:Brigham and Women’s Hospital, Boston, Massachusetts 02241-3149
Project Title: Functional Characterization Of The Mutant Calreticulin-MPL Interaction In Myeloproliferative NeoplasmsProject Summary:
Myeloproliferative neoplasms (MPN) are a group of rare blood cancers that occur when the body produces too many white blood cells, red blood bloods, or platelets. Though the overall prognosis for MPN tends to be favorable, more advanced forms of these diseases can lead to severe anemia, increased risk of blood clots, and transformation to leukemia. MPN were first described in 1951 by hematologist William Dameshek, but the underlying genetic cause of these diseases remained a mystery for over 50 years.
Grant: 1345-18 | Career Development Program (CDP):
Location:The University of Utah, Salt Lake City, Utah 84112-9003
Project Title: MicroRNAs In Myeloid Leukemia Development And Resistance To ChemotherapyProject Summary:
Mutations in genes that control cell growth and survival are commonly found in leukemia. In the case of acute myeloid leukemia (AML) there is often a mutation in a gene called FLT3 that causes it to be activated all the time and promote disease. However, there are many aspects of how this mutated gene is able to promote AML that remain unclear, making it challenging to design and develop new therapies against this devastating condition. My lab studies a newly discovered class of molecules, called microRNAs, which are altered in diseases such as leukemia.
Grant: 5468-18 | Career Development Program (CDP):
Location:New York University School of Medicine, Boston, Massachusetts 02241-415026
Project Title: Understanding The Function Of 3D Chromatin Topology In Myeloid DiseaseProject Summary:
Greater understanding of the fundamental mechanisms promoting the development of acute myeloid leukemia (AML) may help researchers develop new treatment approaches targeting these mechanisms. Chromosomes (collections of DNA and their associated proteins) are heritable and dynamic carriers of genetic information. Chromosomes are constantly looping, and these structural changes shape the gene expression pattern of a cell. This 3D genome landscape, known as genome topology, provides the physical structure required to inform the identity and function of a cell.
Grant: 1351-18 | Career Development Program (CDP):
Location:The Ohio State University, Columbus, Ohio 43210
Project Title: Understanding And Overcoming Resistance To Bruton Tyrosine Kinase Inhibitors In Chronic Lymphocytic LeukemiaProject Summary:
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and until recently was treated with therapies toxic to the patient. Our clinical and research team at The Ohio State University Comprehensive Cancer Center helped provide critical information which led to the FDA approval of ibrutinib, a less toxic targeted therapy. Ibrutinib inhibits the BTK protein, which is a protein that CLL uses for its own pathological survival. Ibrutinib shows remarkable clinical activity that is more durable than any therapy ever studied in CLL.