Intracellular delivery of proapoptotic peptide drugs for the treatment of cancer

描述（由申请人提供）：许多癌症被认为是由具有受损凋亡机制的异常细胞的存活和生长引起的，在正常情况下，这些细胞将经历程序性细胞死亡。已经开发了含有拮抗抗凋亡成员的促凋亡亚组的短肽作为恢复正常凋亡信号传导的手段。然而，能够触发癌细胞凋亡同时避免对健康组织产生毒性的细胞特异性肽类药物尚未实现临床实用性。尽管人们对基于肽的治疗方法充满热情，但仍然存在巨大的障碍，阻碍了它们在晚期癌症患者中的临床应用。维持肽的稳定性和生物活性以及实现靶向的细胞内递送仍然是在这些和其他治疗肽可以应用于体内系统并从而实现其全部潜力之前必须克服的主要障碍。该提案将Stayton实验室的药物递送系统与Press实验室的临床癌症经验结合起来，以开发卵巢癌模型中功能性促凋亡肽递送的初步动物验证。该研究建议的统一假设是促进肿瘤靶向、循环稳定性和促凋亡肽跨细胞内膜的易位将增强其抗肿瘤效力并显著增强其有效性。此外，该项目将评估异种移植模型中抗体靶向的潜力，以使用赫赛汀靶向载体系统增强肿瘤定位。该项目将利用UW Stayton小组和FHCRC Press小组之间强大的跨机构合作，建立强有力的初步数据，以支持未来围绕新的基于肽的卵巢癌疗法的多研究者提案。

DESCRIPTION (provided by applicant): Many cancers are thought to be caused by survival and growth of abnormal cells with impaired apoptotic machinery that, under normal circumstances, would undergo programmed cell death. Short peptides containing pro-apoptotic subgroups that antagonize the anti-apoptotic members have been developed as a means of restoring normal apoptotic signaling. However, cell specific peptide-based drugs that trigger apoptosis in cancerous cells while avoiding toxicity to healthy tissues have not yet achieved clinical utility. Despite the enthusiasm for peptide-based therapeutics, formidable obstacles persist that hinder their clinical application in humans with advanced cancer. Maintaining peptide stability and bioactivity as well as achieving targeted, intracellular delivery remain as major hurdles that must be overcome before these and other therapeutic peptides can be applied to in vivo systems and thereby realize their full potential. This proposal will bring together the Stayton Lab's drug delivery systems with the Press' labs clinical cancer experience to develop preliminary animal validation of functional proapoptotic peptide delivery in an ovarian cancer model. The unifying hypothesis underlying this research proposal is that facilitating tumor targeting, circulation stability, and translocation of proapoptotic peptides across intracellular membranes will augment their anti- tumor potency and substantially enhance their effectiveness. In addition, the project will evaluate the potential of antibody targeting in a xenograft model to enhance tumor localization using a herceptin-targeted carrier system. This project will take advantage of a strong cross-institutional collaboration between the Stayton group at UW and the Press group at the FHCRC to build strong preliminary data to support a future multi-investigator proposal around new peptide-based therapies for ovarian cancer.