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

应聘者描述(由申请人提供)：应聘者是初级调查员，他的职业目标是过渡到波多黎各大学综合癌症中心(UPRCCC)的独立调查员。他的最终目标是成为一名富有成效的独立调查员，能够获得持续的资金来支持他自己的研究计划。他的背景、研究经验和他的出版记录表明，他有能力确定治疗目标，并为卵巢癌开发新的假设驱动、基于机制的策略。在赞助机构(UPRCCC)及其导师/合作者的指导下，制定了有重点的职业发展计划和研究计划。这种培训包括获得科学写作技能，加强生物统计学的主题，以及在导师机构和其他机构发展一个合作者网络。候选人相信，这份补助金申请中概述的职业发展计划和研究计划将有助于他成为UPRCCC的一名独立调查员。在过去的40年里，顺铂一直是治疗卵巢癌最活跃的药物。虽然大多数卵巢癌患者对一线铂联合化疗有反应，但超过70%的患者会复发，导致化疗耐药的致命疾病。因此，迫切需要寻找针对晚期耐药卵巢癌癌细胞生存途径靶点的新疗法。因此，这项建议将解决顺铂耐药和晚期卵巢癌靶向治疗方面的知识空白。哺乳动物靶基因雷帕霉素(MTOR)通路在肿瘤的发生、发展和耐药中起核心作用。因此，mTOR通路已成为重要的癌症治疗靶点，主要与雷帕霉素类似物替西罗莫司(TEMs)一起使用。然而，由于许多癌细胞(包括卵巢癌细胞)对这种化合物具有抗药性，透射电子显微镜的使用受到了阻碍。导致这种抗性的分子机制在很大程度上是未知的。有证据表明，c-myc和c-myc调控基因的激活可能参与了卵巢癌细胞对透射电子显微镜和顺铂的敏感性。因此，我们的总体假设是，c-myc状态水平将决定卵巢癌细胞对透射电子显微镜治疗的敏感性，靶向c-myc基因将使卵巢癌细胞对透射电子显微镜和顺铂治疗敏感。为了验证这一假设，我们将进行以下研究：1)研究小干扰RNA(SiRNA)介导的c-myc靶向在顺铂和泰西莫司耐药卵巢癌细胞中的分子和生物学效应；2)确定c-myc靶向siRNA单独或与体内化疗联合治疗的疗效；3)确定调控耐药卵巢癌细胞c-myc表达的主要细胞内途径。这一建议在评价靶向c-myc以克服卵巢癌细胞对TEM和顺铂耐药性的治疗潜力方面是独一无二的。

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.