The overall goal of this project, led by Prof. Peter Sorger, isto delineate, in precise molecular terms, the mechanisms that regulate the onset of apoptosis in mammalian cells following exposure to small molecule and biological therapeutics. Variation from one cell type to the next and one cell to the next will be an area of particular focus, with the eventual goal of developing means to predict patient-specific responses to therapy. As a means to create mechanistic, probabilistic, integrative and predictive understanding of apoptosis we will collect population-level and single-cell data on caspase activation kinetics and construct, calibrate and analyze a series of mathematical models that describe key steps in mammalian cell death. We will focus largely on existing and investigational anti-cancer drugs, but also expect to examine agents that alter inflammatory and immune responses. Our selection of therapeutic agents is guided by (i) the importance of conventional agents in standard of care cancer treatment and the possibility of developing improved clinical protocols (e.g. taxanes) (ii) the extent of patient-patient variation in drug response and the attendant difficulty of identifying patients who might benefit from a particular treatment (iii) the potential of new agents to significantly improve outcomes as demonstrated by pre-clinical and clinical studies (e.g. ABT-737).
Four specific aims will be pursued involving (1) predictive and mechanistic analysis of pathways controlling mitochondrial outer membrane permeablization and effector caspase activation in cells exposed to ligands that trigger extrinisic apoptosis (2) direct comparison of cell-to-cell variation in the timing and probability of cell death among members of a clonal cell population and between different tumor cell lines (3) experimental and model-driven analysis of intrinsic apoptosis induced by the microtubule poison paclitaxel and the Bcl2 inhibitor ABT737 and single-cell analysis of chemotherapeutics used in combination on diverse cancer cell lines (4) development and application of methods for intravital imaging of mitosis and apoptosis in cancer in situ in the mouse. Success with these aims will impact not only the study of apoptosis, but also general cancer biology and the use of chemotherapeutic drugs

Public Health Relevance

Improving outcomes for patients treated with targeted and cytotoxic chemotherapeutics is critically dependent on understanding mechanisms of tumor killing and patient-to-patient variation in response. We will develop quantitative understanding of cell-to-cell and tumor-to-tumor variation in responses to drugs that target mitotic cells and those that induce apoptosis directly (TRAIL, ABT-737). This understanding will help guide the use of existing drugs and the development of new ones.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA139980-04
Application #
8470477
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$350,921
Indirect Cost
$79,434
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Lee, Robin E C; Qasaimeh, Mohammad A; Xia, Xianfang et al. (2016) NF-κB signalling and cell fate decisions in response to a short pulse of tumour necrosis factor. Sci Rep 6:39519
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
Giedt, Randy J; Fumene Feruglio, Paolo; Pathania, Divya et al. (2016) Computational imaging reveals mitochondrial morphology as a biomarker of cancer phenotype and drug response. Sci Rep 6:32985
Bhola, Patrick D; Mar, Brenton G; Lindsley, R Coleman et al. (2016) Functionally identifiable apoptosis-insensitive subpopulations determine chemoresistance in acute myeloid leukemia. J Clin Invest 126:3827-3836
Roux, Jérémie; Hafner, Marc; Bandara, Samuel et al. (2015) Fractional killing arises from cell-to-cell variability in overcoming a caspase activity threshold. Mol Syst Biol 11:803
Fallahi-Sichani, Mohammad; Moerke, Nathan J; Niepel, Mario et al. (2015) Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis. Mol Syst Biol 11:797
Chittajallu, Deepak R; Florian, Stefan; Kohler, Rainer H et al. (2015) In vivo cell-cycle profiling in xenograft tumors by quantitative intravital microscopy. Nat Methods 12:577-85
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
Miller, Miles A; Zheng, Yao-Rong; Gadde, Suresh et al. (2015) Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug. Nat Commun 6:8692
Flusberg, Deborah A; Sorger, Peter K (2015) Surviving apoptosis: life-death signaling in single cells. Trends Cell Biol 25:446-58

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