With the growing number of therapies being tested in chronic lymphocytic leukemia (CLL) comes the growing challenge of identifying for each patient which therapies are the best. In this competitive renewal proposal, we propose strategies to identify therapeutic opportunities in individual CLL tumors. A key element of this approach is the ability to predict patient response to individual therapies. We apply many of the basic lessons we have learned in the initial grant period about control of apoptosis, and make use of a tool that we refined in that proposal, BH3 profiling. Building on our prior work in which we found we can correlate in vitro sensitivity to ABT-737 to BH3 profiling results, we propose to test our ability to predict clinical response to the related BCL-2 antagonist, ABT-199 in CLL (Specific Aim #1). In addition, in Specific Aim #2, we propose to identify pathway addiction in individual cases of CLL. In the past, inefficiency of siRNA and shRNA approaches and difficulty of ex vivo culture in CLL have made this issue difficult to address by conventional means. We propose a study using small molecule pathway inhibitors instead of knockdown strategies to evade RNA transfection difficulties. Importantly, we use BH3 profiling to measure early apoptotic signaling within 4-24 of drug treatment, obviating the need for extended ex vivo culture.
Our aim i s to link early apoptotic signaling in response to small molecule inhibitors to pathway addiction. An important advantage of this approach is that detection of apoptotic signaling in primary CLL in response to drugs provides a rational path to clinical translation. Finally, in Specific Aim #3, we propose to investigate how stromal interactions inhibit apoptotic signaling in CLL cells. Moreover, using in vitro co-culture systems, we will study the efficacy and mechanisms of drugs intended to interrupt CLL interactions with stromal cells. Our goal is to identify which CLL patients will most benefit from such therapies.

Public Health Relevance

There is a growing number of new and exciting targeted therapies being tested for treating chronic lymphocytic leukemia and other leukemias. However, it is often difficult to predict which patients will benefit most from these therapies, so that thee is a risk of many being treated with drugs that are not useful, and others not getting drugs from which they could benefit. In this proposal, we test a novel strategy, based on our improved understanding of cell death pathways, for matching individual tumors with the drugs that will work best against them to better personalize therapy for chronic lymphocytic leukemia.

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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Jessup, John M
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Dana-Farber Cancer Institute
United States
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Pallis, Monica; Burrows, Francis; Ryan, Jeremy et al. (2017) Complementary dynamic BH3 profiles predict co-operativity between the multi-kinase inhibitor TG02 and the BH3 mimetic ABT-199 in acute myeloid leukaemia cells. Oncotarget 8:16220-16232
Deng, J; Isik, E; Fernandes, S M et al. (2017) Bruton's tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia 31:2075-2084
Sarosiek, Kristopher A; Fraser, Cameron; Muthalagu, Nathiya et al. (2017) Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics. Cancer Cell 31:142-156
Sarosiek, Kristopher A; Letai, Anthony (2016) Directly targeting the mitochondrial pathway of apoptosis for cancer therapy using BH3 mimetics - recent successes, current challenges and future promise. FEBS J 283:3523-3533
Anderson, Mary Ann; Deng, Jing; Seymour, John F et al. (2016) The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 127:3215-24
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Dutta, Sanjib; Ryan, Jeremy; Chen, T Scott et al. (2015) Potent and specific peptide inhibitors of human pro-survival protein Bcl-xL. J Mol Biol 427:1241-53
Winter, Peter S; Sarosiek, Kristopher A; Lin, Kevin H et al. (2014) RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal 7:ra122
Pan, Rongqing; Hogdal, Leah J; Benito, Juliana M et al. (2014) Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov 4:362-75

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