Recent studies have identified small molecule inhibitors of the paracaspase activity of MALT1, a protease and scaffolding protein involved in the B-cell receptor (BCR) signaling pathway, that are effective killing lymphomas in vitro and in vivo in xenograft models of Activated B-cell like Diffuse Large B-cell Lymphoma (ABC-DLBCL). DLBCL is the most common lymphoma and ABC-DLBCL its most chemoresistant subtype. Moreover, the BCR pathway is involved in cell proliferation and survival of several lymphoma subtypes, including follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia/lymphoma. However, not all ABC-DLBCL cell lines and primary patient samples were equally sensitive to MALT1 inhibitors in vitro. Thus, we hypothesize that response to MALT1 inhibitors will be dependent on the genetic background of ABC-DLBCLs, being those holding mutations downstream of MALT1 more likely to be resistant. Likewise, as already reported for other targeted therapies, acquired resistance mechanisms could arise that prevent response to MALT1 inhibitors by either mutation in MALT1 or its downstream targets or by activation of alternative survival pathways. Moreover, lymphoma therapy with drug combinations is the gold standard for the disease and has been proven most effective, thus we hypothesize that MALT1 inhibition will be most valuable in combination with other chemotherapeutic or targeted therapy agents. Consequently, in order to effectively translate MALT1 inhibitors to the clinical practice, our specific aims are: 1) To determine the genetic background of responders to MALT1 inhibition;2) To define possible resistance mechanisms that tumors will deploy to escape therapy and 3) To design and test combination therapies using a holistic approach (rational combination based on actual knowledge of the disease, resistance mechanisms found in Aims 1 and 2 and, unbiased high throughput screening).

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DLBCL is an aggressive type of lymphoma. We developed a MALT1 inhibitor with anti-lymphoma activity selective for ABC-DLBCL, the most unfavorable subtype. We propose to determine the spectrum of lymphomas that respond to MALT1 inhibition and possible resistance mechanisms, and to develop effective drug combinations to effectively translate MALT1 inhibitors to the clinical practice.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Howcroft, Thomas K
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Weill Medical College of Cornell University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Apoorva, F; Loiben, Alexander M; Shah, Shivem B et al. (2018) How Biophysical Forces Regulate Human B Cell Lymphomas. Cell Rep 23:499-511
Fontán, Lorena; Qiao, Qi; Hatcher, John M et al. (2018) Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth. J Clin Invest 128:4397-4412
Saba, Nakhle S; Wong, Deanna H; Tanios, Georges et al. (2017) MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia. Cancer Res 77:7038-7048
Saba, Nakhle S; Liu, Delong; Herman, Sarah E M et al. (2016) Pathogenic role of B-cell receptor signaling and canonical NF-?B activation in mantle cell lymphoma. Blood 128:82-92