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

描述（由申请人提供）：卵巢癌是美国最致命的妇科恶性肿瘤，主要是由于其通常在晚期诊断并最终发展为耐药性。在过去的二十年里，尽管进行了大量的研究，但令人沮丧的5年总生存率仍为30%。RNA干扰（RNAi）是一种基因调控机制，可以通过使用短干扰RNA（siRNA）来特异性抑制导致化疗耐药性的基因。抗凋亡蛋白Bcl-2家族与卵巢癌耐药性的发展有关，并代表了siRNA介导的抑制的有希望的靶点。然而，siRNA的临床实施的主要障碍是有效的肿瘤特异性细胞内递送。本申请将在体内测试由针对Her 2/neu和间皮素的抗体组成的模块化递送系统，以促进卵巢癌细胞对受体介导的细胞内siRNA的摄取，以及pH响应性聚合物，以增强siRNA的内体逃逸到细胞质中。该项目的目标是：1）证明和优化Her 2/neu和间皮素介导的siRNA体内递送; 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和卡铂在腹膜内卵巢癌的小鼠异种移植模型中增加存活的组合功效。这项研究建立在申请人玛丽亚·科琳娜·帕兰卡-韦茨医学博士以前非常有前途的工作的基础上，博士，并包括职业发展计划的一部分，这将使她能够成功地过渡到一个完全独立的研究职位。她的长期目标是建立一个转化研究计划，以测试新的癌症疗法，利用肿瘤特异性抗原和RNA干扰更有效地治疗恶性肿瘤。她的导师，奥利弗W。Press，M.D.，哲学博士、和一个精心挑选的K 08咨询委员会是在免疫治疗，聚合物技术，细胞内siRNA输送和卵巢癌的相关领域的受人尊敬的领导者。Press博士是一位世界知名的内科科学家，在指导初级教师从事癌症研究的独立职业方面有着良好的记录。他是一位杰出的导师，将为她提供丰富的资源和帮助，以实现她的职业目标。Press和Palanca-Wessels博士已经准备了一个职业发展计划，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取结合起来。Press和她的K 08咨询委员会将在指导她走向新的研究方向方面发挥重要作用，以申请独立资助并实现她成为抗体和RNAi领域专家的长期目标。此外，她将利用现有的资源， 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.