Intracellular delivery of proapoptotic peptide drugs for the treatment of cancer

描述(申请人提供)：许多癌症被认为是由异常细胞的存活和生长引起的，这些细胞的凋亡机制受损，在正常情况下，会经历细胞程序性死亡。含有促凋亡亚基的短肽可拮抗抗凋亡成员，已被开发为恢复正常凋亡信号的一种手段。然而，基于细胞特异性多肽的药物在诱导癌细胞凋亡的同时避免对健康组织的毒性，尚未获得临床应用。尽管人们对基于多肽的疗法充满热情，但巨大的障碍仍然存在，阻碍了它们在晚期癌症患者的临床应用。维持多肽的稳定性和生物活性以及实现有针对性的细胞内递送仍然是这些和其他治疗性多肽应用于体内系统从而实现其全部潜力之前必须克服的主要障碍。这项建议将把Stayton Lab的药物输送系统与Press实验室的癌症临床经验结合起来，开发卵巢癌模型中功能性促凋亡肽输送的初步动物验证。支持这项研究建议的统一假设是，促进肿瘤靶向性、循环稳定性和促凋亡多肽跨细胞膜转移将增强其抗肿瘤效力，并显著增强其有效性。此外，该项目将评估在异种移植模型中使用赫赛汀靶向载体系统增强肿瘤定位的抗体靶向的潜力。该项目将利用威斯康星大学的Stayton小组和FHCRC的Press小组之间强大的跨机构合作来建立强大的初步数据，以支持未来围绕卵巢癌新的基于多肽的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.