Treatment of human cancers with chemotherapy or radiation with curative intent has led to the successful eradication of malignancies in millions of patients, yet the apoptotic cell death induced in healthy tissues drastically limits the use of thee crucial therapies. This is especially true in pediatric patients that, for example, commonly experience cardiotoxicity from doxorubicin treatment or neuronal apoptosis after brain irradiation. Adults exhibit dramatically less toxicity than children from these same treatments but the basis for this difference in sensitivity is unknown. Using BH3 profiling, an innovative tool to measure how close cells are to the threshold of apoptosis, we recently observed novel and striking differences in the how apoptosis is regulated in vital tissues that challenge the existing dogma in the field. These observations also create opportunities to improve existing therapies and develop novel classes of anti-cancer drugs. Within this proposal, we plan to first develop a comprehensive understanding of how differential regulation of apoptosis affects cell fate in response to damage or stress in vivo (Aim 1). Using gene expression analysis and mouse models, we will then identify the molecular mechanisms that control these pathways (Aim 2). Finally, we will utilize our newfound knowledge to identify and develop agents that will reduce toxicity from current treatments or represent novel classes of anti-cancer therapies (Aim 3). By understanding and modulating apoptosis programs in healthy and cancerous cells we will improve patient outcomes.

Public Health Relevance

The regulation of cell death pathways in healthy cells is difficult to study and represents an alarming gap in our knowledge considering the importance of maintaining survival in the cells that make up vital tissues. Utilizing a novel assay that allows u to meaningfully measure how ready cells are to undergo cell death (apoptosis), we have begun to observe novel and unexpected ways that cells maintain their survival that, within this proposal, will be characterized and exploited for patient benefit.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Career Transition Award (K99)
Project #
1K99CA188679-01
Application #
8767377
Study Section
Subcommittee B - Comprehensiveness (NCI)
Program Officer
Schmidt, Michael K
Project Start
2014-09-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02215
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
Gunda, Viswanath; Sarosiek, Kristopher A; Brauner, Eran et al. (2017) Inhibition of MAPKinase pathway sensitizes thyroid cancer cells to ABT-737 induced apoptosis. Cancer Lett 395:1-10
P├ęcot, Jessie; Maillet, Laurent; Le Pen, Janic et al. (2016) Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance. Cell Rep 17:3347-3358
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
Montero, Joan; Sarosiek, Kristopher A; DeAngelo, Joseph D et al. (2015) Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy. Cell 160:977-989
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