Targeting c-MYC Overcomes Temsirolimus and Cisplatin Resistance of Ovarian Cancer

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DESCRIPTION (provided by applicant): The Candidate is a Junior Investigator and his career goals are to transition into an independent investigator at the University of Puerto Rico Comprehensive Cancer Center (UPRCCC). His ultimate goal is to become a productive, independent investigator able to obtain continuous funding to support his own research program. His background, research experience and his record of publications demonstrate his ability to identify therapeutic targets and develop novel hypothesis-driven, mechanism-based strategies for ovarian cancer. A focused Career Development Plan and Research Plan have been designed under the direction of the sponsor institution (UPRCCC), and his mentors/collaborators. This training includes acquiring scientific writing skills, reinforcement of biostatistics' topics, and development of a network of collaborators at the mentors' institution and in other institutions. The Candidate is confident that the Career Development Plan and Research Plan outlined in this grant application will aid in his establishment as an independent investigator in the UPRCCC. Cisplatin has been the most active drug for the treatment of ovarian cancer for the last 4 decades. Although the majority of patients with ovarian cancer respond to front-line platinum combination chemotherapy, relapse occurs in over 70% of patients, resulting in chemoresistant, fatal disease. Therefore, there is an urgent need to find new therapies focused on targets within cancer cell survival pathways for advanced stage drug resistant ovarian cancer. Thus, this proposal will address a gap in knowledge on targeted therapy for cisplatin resistant and advanced ovarian cancer. The mammalian target of rapamycin (mTOR) pathway plays a central role in cancer initiation, progression, and drug resistance. Thus, the mTOR pathway has emerged as an important cancer therapeutic target, principally with the rapamycin analog, temsirolimus (TEM). However, the use of TEM has been hampered because many cancer cells (including ovarian cancer cells) are resistant to this compound. The molecular mechanisms responsible for this resistance are largely unknown. Evidence indicates that the activation of c-MYC and c-MYC-regulated genes could be involved in the sensitivity of ovarian cancer cells to TEM and cisplatin treatment. Thus, our overall hypothesis is that c-MYC status levels will determine the sensitivity of ovarian cancer cells to TEM treatment, and that targeting c-MYC will sensitize ovarian cancer cells to TEM and cisplatin treatment. To test this hypothesis we will pursue the following lines of research: 1) Investigate the molecular and biological effects of small interference RNA (siRNA)-mediated targeting of c- MYC in cisplatin and temsirolimus-resistant ovarian cancer cells, 2) Determine the therapeutic efficacy of c- MYC-targeted siRNA alone or in combination with chemotherapy in vivo, and 3) Identify the major intracellular pathways regulating c-MYC expression in drug resistant ovarian cancer cells. This proposal is unique in the evaluation of the therapeutic potential of targeting c-MYC to overcome TEM and cisplatin resistance of ovarian cancer cells.