It has been hypothesized that cancer cells require a block in apoptosis for survival, due to their numerous phenotype irregularities. One potential mechanism cancer cells might exploit to maintain survival is the expression of antiapoptotic proteins of the BCL-2 family. We have developed a novel method, called BH3 profiling, that detects dependence on antiapoptotic proteins. It is particularly useful as it can be used to study freshly isolated primary cancer tissues without need for further culture ex vivo. We will use this and other more standard techniques to study regulation of apoptosis in several systems. First, we will investigate whether chronic lymphocytic leukemia (CLL) cells are dependent on BCL-2 for survival. We will also examine whether CLL cells are sensitive to treatment with a novel BCL-2 antagonist, ABT-737. We will furthermore determine the molecular events underpinning this sensitivity. Next, we will investigate acquired resistance to BCL-2 antagonism. We have identified a panel of hematopoietic cancer cell lines that are sensitive to ABT-737 treatment. Since acquired resistance to therapy is an important clinical phenomenon, we will study the molecular mechanisms by which cells might become resistant to ABT-737. Identification of these mechanisms will be critical to designing therapies to overcome resistance. We propose a series of mechanism-based combination therapies to be tested for their ability to overcome resistance and facilitate response to ABT-737 in cell lines and CLL cells. Finally, our studies to date suggest that cancer cells are far more likely to be dependent on anti-apoptotic proteins than non-malignant, normal cells. We will test this hypothesis by systematically evaluating the anti-apoptotic requirements of normal blood cells using BH3 profiling. Our goal is to provide a molecular understanding of what may be a dichotomy of vital clinical significance, as it suggests an intriguing therapeutic window between normal and cancer cells. These studies are directed at determining the specific ways cancer cells keep themselves alive, ways that may be used only by cancer cells, but not by normal, healthy cells. Understanding this would allow us to identify targets that would kill cancer cells, but not normal cells. Such a strategy has the promise to improve treatment of cancer by making treatment more selective for cancer cells, and therefore less toxic to normal, healthy tissues.

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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Arya, Suresh
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Dana-Farber Cancer Institute
United States
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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
Touzeau, C; Ryan, J; Guerriero, J et al. (2016) BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics. Leukemia 30:761-4
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
Montero, Joan; Sarosiek, Kristopher A; DeAngelo, Joseph D et al. (2015) Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 160:977-89
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
Chonghaile, Triona Ni; Roderick, Justine E; Glenfield, Cian et al. (2014) Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov 4:1074-87
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
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
Hogdal, Leah J; Letai, Anthony (2013) BCL-2 inhibition: stemming the tide of myeloid malignancies. Cell Stem Cell 12:269-70
Sarosiek, Kristopher A; Ni Chonghaile, Triona; Letai, Anthony (2013) Mitochondria: gatekeepers of response to chemotherapy. Trends Cell Biol 23:612-9

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