Antibody directed delivery of short interfering RNA for the treatment of ovarian

描述(申请人提供)：卵巢癌是美国最致命的妇科恶性肿瘤，主要是因为它通常在晚期被诊断出来，并最终产生耐药性。尽管进行了密集的研究工作，但在过去20年里，令人沮丧的30%的5年总体存活率基本保持不变。RNA干扰(RNAi)是一种基因调控机制，可以通过使用短干扰RNA(SiRNA)来特异性地抑制与化疗耐药有关的基因。抗凋亡蛋白Bcl2家族参与了卵巢癌耐药的发生，是siRNA介导抑制肿瘤耐药的良好靶点。然而，siRNA临床应用的一个主要障碍是有效的肿瘤特异性细胞内递送。这一应用将在体内测试一种模块化递送系统，该系统由针对Her2/neu和Mesothelin的抗体组成，以促进卵巢癌细胞通过受体介导的细胞内siRNA摄取，以及一种pH响应型聚合物，以增强siRNA内体逃逸到细胞质中。本项目的目的是：1)验证和优化Her2/neu和Mesothelin介导的siRNA在体内的传递；2)评估针对Bcl-2家族成员的siRNA对卡铂的细胞毒性增强作用；3)测试促凋亡siRNA和卡铂对提高小鼠腹膜内卵巢癌移植瘤模型存活的联合疗效。这项研究建立在申请者Maria Corinna Palanca-Wessels医学博士之前非常有前途的工作基础上，并包括使她能够成功过渡到完全独立的研究职位的职业发展计划的一部分。她的长期目标是建立一个转译研究计划，以测试利用肿瘤特异性抗原和RNA干扰更有效地治疗恶性肿瘤的新型癌症疗法。她的导师奥利弗·W·普莱斯博士和精心挑选的K08咨询委员会是免疫治疗、聚合物技术、细胞内siRNA递送和卵巢癌相关领域受人尊敬的领导者。普莱斯博士是一位世界知名的内科科学家，在指导初级教师在癌症研究领域从事富有成效的独立职业方面有着良好的记录。他是一位杰出的导师，将为她提供充足的资源和帮助，以实现她的职业目标。Press博士和Palanca-Wessels博士已经准备了一份职业发展计划，该计划将RNA生物学、药物开发和生物统计学领域的教学课程与实验室技能的实际获得相结合。与普莱斯博士和她的K08顾问委员会的定期进展会议将在引导她走向新的研究方向方面发挥重要作用，以期申请独立资金，并实现她成为卵巢癌治疗中抗体和基于RNAi的疗法领域的专家的长期目标。此外，她将利用尚未到位的资源 由弗雷德·哈钦森癌症研究中心和华盛顿大学提供，以促进她的职业发展。

DESCRIPTION (provided by applicant): Ovarian cancer is the most deadly gynecologic malignancy in the United States principally due to its usual diagnosis at an advanced stage and eventual development of drug resistance. A dismal 5-year overall survival rate of 30% has remained largely unchanged over the past two decades despite intensive research efforts. RNA interference (RNAi) is a mechanism of gene regulation that can be manipulated through the use of short interfering RNA (siRNA) to specifically suppress genes that contribute to chemotherapy resistance. The Bcl-2 family of anti-apoptotic proteins have been implicated in the development of drug resistance in ovarian cancer and represent promising targets for siRNA mediated inhibition. However, a major hurdle for clinical implementation of siRNA is effective tumor-specific intracellular delivery. This application will test in vivo a modular delivery system consisting of antibodies directed against Her2/neu and mesothelin to promote receptor-mediated intracellular siRNA uptake by ovarian cancer cells and a pH-responsive polymer to enhance endosomal escape of siRNA into the cytoplasm. The project aims are to: 1) demonstrate and optimize Her2/neu and mesothelin mediated siRNA delivery in vivo; 2) evaluate siRNA directed against Bcl-2 family members for cytotoxic potentiation of carboplatin 3) test the combined efficacy of proapoptotic siRNA and carboplatin to augment survival in a mouse xenograft model of intraperitoneal ovarian cancer. This research builds upon previous highly promising work by the applicant, Maria Corinna Palanca-Wessels M.D., Ph.D, and comprises part of a career development plan that will enable her to successfully transition into a fully independent research position. Her long-term goal is to establish a translational research program to test novel cancer therapies that exploit tumor specific antigens and RNA interference for more effective treatment of malignancies. Her mentor, Dr. Oliver W. Press, M.D., Ph.D., and a carefully selected K08 advisory committee are respected leaders in the relevant fields of immunotherapy, polymer technology, intracellular siRNA delivery and ovarian cancer. Dr. Press is a world-renowned physician scientist with an established track record of guiding junior faculty to productive independent careers in cancer research. He is an outstanding mentor and will provide her with abundant resources and assistance to achieve her career objectives. Drs. Press and Palanca-Wessels have prepared a career development plan that will integrate didactic coursework in the fields of RNA biology, drug development, and biostatistics with practical acquisition of laboratory skills at the benchside. Regular progress meetings with Dr. Press and her K08 advisory committee will serve an important role in guiding her toward new research directions in anticipation of applying for independent funding and achieving her long-term goal of becoming an expert in the fields of antibody and RNAi-based therapeutics for ovarian cancer treatment. Additionally, she will utilize the outstanding resources offered by both the Fred Hutchinson Cancer Research Center and the University of Washington to foster her career development.