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

靶向 c-MYC 克服卵巢癌的替西罗莫司和顺铂耐药性

• 批准号: 8442584
• 负责人: Pablo Elias Vivas-Mejia
• 金额: $ 18.14万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-07 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442584
• 关键词: Address; Applications Grants; Biological; Biometry; CCI-779; Cancer Patient; Cancer cell line; Cell Cycle; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cells; Cessation of life; Cisplatin; Combination Drug Therapy; Comprehensive Cancer Center; Data; Development; Development Plans; Diagnosis; Disease; Down-Regulation; Drug resistance; Feedback; Funding; Genes; Genome; Glioblastoma; Goals; Human; Institution; JUN gene; Knowledge; Liposomes; MAPK8 gene; MYC Family Protein; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mediating; Mentors; Messenger RNA; Metabolism; MicroRNAs; Molecular; Molecular Medicine; Ovarian Serous Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Platinum; Play; Protein Biosynthesis; Proteins; Psychological reinforcement; Publications; Puerto Rico; RNA Interference; Relapse; Research; Research Personnel; Research Project Grants; Resistance; Role; Sirolimus; Staging; Testing; The Cancer Genome Atlas; Training; Treatment Efficacy; United States; Universities; Woman; Writing; base; cancer cell; cancer initiation; career; career development; cell type; chemotherapeutic agent; chemotherapy; design; experience; functional genomics; in vivo; inhibitor/antagonist; mTOR protein; novel; overexpression; programs; research and development; research study; skills; therapeutic evaluation; therapeutic target; trend; tumor; tumor growth

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.

描述（由申请人提供）：候选人是一名初级研究员，他的职业目标是过渡到波多黎各大学综合癌症中心（UPRCCC）的独立研究员。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自己的研究计划。他的背景，研究经验和他的出版物记录表明，他有能力确定治疗靶点，并为卵巢癌开发新的假设驱动的，基于机制的策略。在赞助机构（UPRCCC）及其导师/合作者的指导下，设计了一个重点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建立合作者网络。候选人有信心，职业发展计划和研究计划概述了本补助金申请将有助于他建立作为一个独立的调查员在UPRCCC。顺铂是近40年来治疗卵巢癌最有效的药物。虽然大多数卵巢癌患者对一线铂类联合化疗有反应，但超过70%的患者会复发，导致化疗耐药，致命性疾病。因此，迫切需要找到针对晚期耐药卵巢癌癌细胞存活途径内靶点的新疗法。因此，该提案将解决顺铂耐药和晚期卵巢癌靶向治疗知识的空白。哺乳动物雷帕霉素靶蛋白（mTOR）通路在癌症的发生、发展和耐药性中起着重要作用。因此，mTOR途径已经成为重要的癌症治疗靶点，主要是雷帕霉素类似物坦罗莫司（TEM）。然而，TEM的使用受到阻碍，因为许多癌细胞（包括卵巢癌细胞）对这种化合物具有耐药性。负责这种耐药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卵巢癌细胞对TEM和顺铂治疗的敏感性。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TEM治疗的敏感性，并且靶向c-MYC将使卵巢癌细胞对TEM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）介导的靶向c-MYC在顺铂和替西罗莫司抗性卵巢癌细胞中的分子和生物学效应，2）确定单独或与化疗组合的c-MYC靶向siRNA的体内治疗功效，和3）鉴定在耐药卵巢癌细胞中调节c-MYC表达的主要细胞内途径。该提议在评估靶向c-MYC以克服卵巢癌细胞的TEM和顺铂耐药性的治疗潜力方面是独特的。