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

抗体定向递送短干扰RNA治疗卵巢癌

• 批准号: 8374090
• 负责人: MARIA Corinna PALANCA-WESSELS
• 金额: $ 17.06万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-06 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8374090
• 关键词: Advisory Committees; Antibodies; Apoptosis; Apoptotic; Binding; Biodistribution; Biology; Biometry; Cancer Patient; Cancer cell line; Carboplatin; Cell Surface Receptors; Cell Survival; Cells; Cessation of life; Chemosensitization; Clinical; Colon; Coupling; Cytoplasm; DNA Repair; Development; Development Plans; Diagnosis; Disease; Doctor of Medicine; Doctor of Philosophy; Double-Stranded RNA; Drug Delivery Systems; Drug Kinetics; Drug resistance; ERBB2 gene; Effectiveness; Epidermal Growth Factor Receptor; Epithelial; Epithelial ovarian cancer; Faculty; Failure; Family; Family member; Fostering; Fred Hutchinson Cancer Research Center; Funding; Gene Expression Regulation; Gene Targeting; Genes; Goals; Gynecologic; Immunotherapy; In Vitro; Laboratories; Link; Lung; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of esophagus; Malignant neoplasm of ovary; Malignant neoplasm of urinary bladder; Mediating; Membrane; Mentors; Messenger RNA; Methods; Micelles; Mus; Nucleic Acids; Ovarian; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Physicians; Platinum; Polymers; Positioning Attribute; Primary Cell Cultures; Proteins; RNA; RNA Interference; RNA Interference Pathway; RNA Sequences; RNA-Induced Silencing Complex; Receptor Protein-Tyrosine Kinases; Recurrence; Regimen; Research; Research Project Grants; Resistance; Resources; Role; Salvage Therapy; Scientist; Screening procedure; Signal Transduction; Site; Staging; Streptavidin; Surface; Survival Rate; Symptoms; System; Technology; Testing; Therapeutic; Toxic effect; Translational Research; Tumor Antigens; Tumor-Derived; United States; Universities; Washington; Work; Xenograft Model; Xenograft procedure; antibody conjugate; anticancer research; base; cancer cell; cancer diagnosis; cancer therapy; career; career development; chemotherapy; clinically relevant; cytotoxic; cytotoxicity; drug development; drug sensitivity; effective therapy; improved; in vivo; intraperitoneal; malignant stomach neoplasm; meetings; mesothelin; mouse model; neoplastic cell; novel; outcome forecast; ovarian neoplasm; overexpression; prevent; programs; receptor; response; skills; statistics; tumor; uptake

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.

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产生耐药性。尽管进行了大量的研究工作，但过去二十年里，30% 的令人沮丧的 5 年总体生存率基本保持不变。 RNA 干扰 (RNAi) 是一种基因调控机制，可以通过使用短干扰 RNA (siRNA) 来特异性抑制导致化疗耐药的基因。 Bcl-2 抗凋亡蛋白家族与卵巢癌耐药性的发展有关，并且是 siRNA 介导的抑制的有希望的靶标。然而，siRNA临床实施的一个主要障碍是有效的肿瘤特异性细胞内递送。该应用将在体内测试模块化递送系统，该系统由针对 Her2/neu 和间皮素的抗体组成，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) 演示和优化 Her2/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 和卡铂的联合功效，以提高小鼠腹膜内卵巢癌异种移植模型的存活率。这项研究建立在申请人 Maria Corinna Palanca-Wessels 医学博士、博士之前非常有前途的工作的基础上，并且是职业发展计划的一部分，该计划将使她能够成功过渡到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来测试新型癌症疗法，利用肿瘤特异性抗原和 RNA 干扰来更有效地治疗恶性肿瘤。她的导师 Oliver W. Press 博士（医学博士、哲学博士）和精心挑选的 K08 顾问委员会都是免疫治疗、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。 Press 博士是一位世界知名的医学科学家，在指导初级教师在癌症研究领域开展富有成效的独立职业方面有着良好的记录。他是一位出色的导师，将为她提供丰富的资源和帮助来实现她的职业目标。博士。 Press 和 Palanca-Wessels 准备了一份职业发展计划，该计划将把 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。与 Press 博士和她的 K08 咨询委员会定期举行进展会议，将在指导她走向新的研究方向方面发挥重要作用，以期申请独立资助并实现她成为卵巢癌抗体和 RNAi 疗法领域专家的长期目标。此外，她还将利用优秀的资源 由弗雷德·哈钦森癌症研究中心和华盛顿大学共同提供，以促进她的职业发展。