Grant: 6516-17 | Translational Research Program (TRP):
Location:The University of Chicago, Chicago, Illinois 60637
Project Title: Overcoming Ibrutinib Resistance In CLL By Dual SYK/JAK Inhibition With A Single Agent CerdulatinibProject Summary:
Therapies targeting B-cell receptor (BCR) signaling pathway in CLL tumor cells, such as ibrutinib, are very effective with ~90% of patients responding to the drug initially. However, since the primary action of the drug is not cell killing, CLL cells, although under control, are not totally eliminated. The malignant cells then have an opportunity undergoing mutation and developing resistance to the drug then causing disease relapse. Once patients relapse, their outcomes are poor with only a few months of survival.
Grant: 5450-17 | Career Development Program (CDP):
Location:Boston Children's Hospital, Boston, Massachusetts 02241-4413
Project Title: Investigating The Roles Of Alternative End Joining In Immunoglobulin Class Switch RecombinationProject Summary:
Class switch recombination (CSR) generates different classes of antibodies to optimize immune responses. This process involves programmed formation and repair of DNA breaks in the antibody gene region. Failure to fix these breaks can lead to chromosomal translocation, a hallmark of mature B cell lymphomas. Indeed, more than 50% of mature B cell lymphomas carry chromosomal translocations that recur among different patients and that are highly associated with particular cancer subtypes.
Grant: 3364-17 | 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
Project Title: The Role Of The Vav1 Mutations In Peripheral T-cell LymphomasProject Summary:
Lymphomas are malignant tumors derived from lymphocytes, blood cells responsible for fighting infection. Peripheral T-cell lymphomas are some of the most aggressive and difficult to treat forms of this disease. As a result, they are frequently associated with very poor prognosis. We propose that improved understanding of the mechanisms implicated in this disease will facilitate the development of new and more effective therapies. In this context, we have identified mutations in the VAV1 gene in lymphoma samples from peripheral T-cell lymphoma patients.
Grant: 5456-17 | Career Development Program (CDP):
Location:The Trustees of the University of Pennsylvania, Medical Center, Philadelphia, Pennsylvania 19104-6205
Project Title: Elucidating The Notch:Myc Signaling Axis In Mantle Cell Lymphoma (MCL)Project Summary:
Mantle cell lymphoma (MCL) is an aggressive blood cancer of mature B cells. Despite a variety of treatments designed to target signaling pathways responsible for its pathogenesis, MCL is currently incurable. Thus, novel treatment approaches are needed. An important contributor to MCL, especially in highly aggressive variants, is over-activated Notch signaling. Notch is a receptor that when activated by either ligand or mutation functions to regulate the expression of genes involved in cell fates, growth, survival and metabolism.
Grant: 6523-17 | Translational Research Program (TRP):
Location:Weill Cornell Medical College, New York, New York 10022
Project Title: Algorithmically-driven Personalized Combination Therapy For Chronic Lymphocytic LeukemiaProject Summary:
Genetic research of chronic lymphocytic leukemia (CLL) provided key insights as to why despite effective therapies this leukemia remains incurable. We and others have found that CLLs are in fact composed of multiple smaller populations that are genetically distinct one from another. In each patient, we are dealing not with a single disease entity, but rather with a collection of multiple diverse populations.
Grant: 6525-17 | Translational Research Program (TRP):
Location:Massachusetts General Hospital, Boston, Massachusetts 02241-4876
Project Title: A Multi-Peptide Vaccine With Lenalidomide And PD-L1 Blockade For Smoldering Multiple Myeloma.Project Summary:
Smoldering Multiple Myeloma (SMM) is a precursor asymptomatic, plasma cell disorder with all the diagnostic hallmarks of MM in the absence of symptoms. Although asymptomatic, SMM is associated with a high risk of progression to symptomatic MM which is currently incurable. The risk of progression is contingent upon several features including amount of monoclonal protein, presence of plasma cells in the bone marrow and abnormal free light chain ratio. The current standard of care for these patients remains watchful waiting.
Grant: R6506-17 | Translational Research Program (TRP):
Location:Icahn School of Medicine at Mount Sinai, New York, New York 10029
Project Title: Treatment Strategies For MPN By Targeting The Tumor Suppressor P53Project Summary:
The myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), affect over 200,000 individuals in the United States. The drugs currently used to treat PV and ET reduce the risk of thrombosis and hemorrhage, relieve symptoms, but do not prevent evolution to MF or acute myeloid leukemia (AML). Hematopoietic stem cell (HSC) transplantation provides an opportunity for cure but, only a fraction of patients with advanced MF are appropriate for this option.
Grant: 3367-17 | Career Development Program (CDP):
Location:University of Toronto, Toronto, Ontario M5S 1S8
Project Title: Targeting VCP/p97 As A Therapeutic Strategy In Multiple MyelomaProject Summary:
The viability of multiple myeloma cells is dependent on protein quality control processes. Approaches based on inhibition of key players in this process, such as the proteasome via bortezomib, have been used successfully to treat blood cancers. p97/VCP (valosin-containing protein), one of the most abundant mammalian proteins, is central for regulating various aspects of protein quality control and DNA repair. Inhibition of p97 has recently been suggested as an alternative therapeutic avenue to treat multiple myeloma, with potential even in cases of resistance to proteasome inhibitors.
Grant: RTF6000-17 | RTFCCR/ LLS Patient-Focused Immunotherapy Research Grant for Blood Cancer:
Location:Baylor College of Medicine, Houston, Texas 77030
Project Title: Multi-tumor Antigen-targeted T Cell Therapy For AMLProject Summary:
This application seeks to harness the killing capacity of the immune system to eliminate acute myeloid leukemia (AML). AML is a frequently diagnosed blood cancer that is in need of new therapies, as patient suffering from high-risk disease have little chance of cure. To achieve our goal of developing an effective immunotherapy for AML we will utilize a specific type of immune cell called T-cell, which has a natural ability to seek out and kill malignant cells while leaving normal cells unharmed. Hence, this type of approach is both safe (non-toxic) and highly effective.
Grant: 5454-17 | Career Development Program (CDP):
Location:Dana-Farber Cancer Institute, Boston, Massachusetts 02215
Project Title: Mechanisms Linking Centrosome Amplification To A Pro-invasive Secretory Program And Cancer.Project Summary:
In many types of cancers, including blood cancers, tumor cells contain extra copies of a cellular structure called the centrosome. Centrosomes assemble a structural network of filaments known as microtubules that is involved in cellular processes such as secretion and migration. We recently demonstrated that the acquisition of extra centrosomes hyperactivates Rac-1, the tumor-promoting, small G-protein, which can drive metastasis. However, the mechanistic link between extra centrosomes and Rac-1-mediated metastasis remains unclear.