Engaging the cell death pathway known as apoptosis is critical for the success of many anti-cancer agents, both novel targeted agents and conventional cytotoxic agents. Whether the chemotherapy is conventional cytotoxic chemotherapy, or more modern targeted therapy, it is usually the case that while the initial target is known, the signaling downstream ofthe target that connects it to the intrinsic apoptotic pathway is poorly understood. Therefore, key molecular determinants of sensitivity and resistance to chemotherapy are largely unknown. The consequence, is that we are very bad at predicting what tumors respond to chemotherapy and why. Thus, many patients are exposed to toxic drugs without a good chance at response. Here we propose a systematic approach to connecting the contact of drug to upstream target to the commitment to programmed cell death at the mitochondrion. Since the BCL-2 family of proteins are the key regulators of mitochondrial apoptosis, they will be studied in particular detail. Our goals are to identify complete signaling pathways that are invoked when tumors are killed by anti-mitotic agents or ABT-737. We will use this information to generate predictive models that can predict sensitivity to treatment based solely on certain defined initial conditions. Once these predictive models are validated in in vitro models, we will apply to clinical testing. Furthermore, understanding the signaling pathways that permit successful killing by taxanes may permit the identification of targets in the pathway that can be selectively exploited by less toxic agents. The techniques we will use will include siRNA screening for genes that are essential for priming the apoptotic pathway. In addition, we have developed a new strategy which we call FACS-based BH3 profiling, that allows us to observe, at the single cell level, a cell's death signaling during progression to mitochondrial apoptosis. This strategy will permit a more detailed analysis ofthe role ofthe cell cycle and the role of individual molecules in determining death after treatment with anti-mitotic agents.

Public Health Relevance

Chemotherapy is used to treat most cancers, yet some basic questions remain unanswered. We are attempting to better understand whay chemotherapy kills some cells but not others. We will attempt to detemine why some cancer cells are resistant to chemotherapy while others are sensitive, using this knowledge to generate more effective treatment strategies

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-O)
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Harvard University
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