Targeting HSP70 in CARM1-expressing epithelial ovarian cancer

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PROJECT SUMMARY The goals of this NCI Pathway to Independence Career Development proposal are to request support for training to develop expertise in developing novel therapeutic strategies for ovarian cancer while investigating the role of coactivator-associated arginine methyltransferase 1 (CARM1) in promoting sensitivity to HSP70 inhibition. K99/R00 support during this part of my career will be integral to my successful development as an independent cancer researcher. The training plan outlined in this proposal will take advantage of the extensive resources at The Wistar Institute, University of Pennsylvania as well as Temple University. My training will also be guided by the advisory committee who have successfully mentored multiple predoctoral, postdoctoral, and clinical fellows in academic careers. The scientific portion of this proposal focuses on experimentally determining the molecular mechanism underlying the sensitivity of CARM1-expresing ovarian cancer cells to HSP70 inhibition. The proposed studies are based on my previous findings that CARM1 is often overexpressed and functions as an oncogene in ovarian cancer patients. High-grade serous ovarian cancer (HGSOC) has the highest rate of CARM1 amplification and overexpression (~20% combined) among all cancer types. Moreover, high CARM1 levels are associated with poor survival in EOC patients. Thus, it is imperative to develop novel approaches to target CARM1-expressing EOC. My preliminary data suggest CARM1-expressing cells are selectively sensitive to HSP70 inhibition. HSP70 is a crucial part of the protein folding machinery and its levels are upregulated in multiple types of cancer. Interestingly, HSP70 is a substrate for CARM1’s enzymatic activity. However, the effect of HSP70 modification by CARM1 is not fully understood. Thus, the major goal of this proposal is to determine whether CARM1- expressing EOC can be treated and ultimately eradicated by novel therapeutic strategies based on HSP70 inhibition. Therefore, I will explore the following scientific aims: 1) To elucidate the mechanistic basis underlying the selectivity against CARM1-high cells by HSP70 inhibition by using gain and loss of function assays in CARM1-high and CARM1-low expressing EOC cells. 2) To develop novel therapeutic strategies for CARM1- expressing EOCs based on HSP70 inhibition. The completion of the scientific aims in this proposal will help develop my research skills and knowledge in the field of ovarian cancer and will lay a critical foundation to establish the use HSP70 inhibitors in CARM1-high EOCs as a single agent or in combination with other promising small-molecule inhibitors such as EZH2 inhibitors.