E2F-1 Cancer Gene Therapy

E2F-1癌症基因治疗

• 批准号: 6642806
• 负责人: Kelly M McMasters
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642806
• 关键词: CD95 molecule; antineoplastics; apoptosis; biological signal transduction; camptothecin; cell growth regulation; cell line; combination therapy; doxorubicin; drug resistance; gene therapy; genetic transduction; mitogen activated protein kinase; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplastic cell; northern blottings; temozolomide; transcription factor; western blottings

DESCRIPTION (PROVIDED BY APPLICANT): The major reason for the failure of anticancer drug therapy in most advanced solid tumors is the presence of chemotherapy-resistant tumor cells. Apoptosis is now considered to be an essential event in antitumor drug induced death. Therefore, cells with deficient apoptotic pathways may be incapable of producing an efficient apoptotic response, regardless of the agent to which they are exposed. For this reason, gene therapy using proapoptotic genes that can either trigger apoptosis in chemo-resistant cells or reconstitute the apoptotic pathway to enhance chemotherapy is a potential therapeutic strategy. The transcription factor, E2F-1, has recently been identified as a potent tumor suppressor. We and others have shown that E2F- 1 overexpression efficiently induces apoptosis in a variety of tumor types, independent of p53 status, both in vitro and in vivo. However, the mechanisms by which E2F-1 induces apoptosis remain ill defined. Mechanistically, our preliminary data implicate activation of the Fas death receptor pathway, involving ASK1, JNK, p38, and ERK MAP kinases in E2F- 1-mediated apoptosis, a novel finding. Furthermore, NFkappaB activation and downregulation of inhibitors of apoptosis (IAPs, specifically XIAP and cIAP-1) and the antiapoptotic Bcl-2 family member, Mcl-1 were seen after E2F-1- overexpression, again novel findings. Furthermore, our preliminary studies indicate that topoisomerase I and II agents, and the drug temozolomide work cooperatively with E2F-1 to induce apoptosis in colon cancer and melanoma cells in vitro and in vivo. Based on substantial preliminary data and the existing literature, we have proposed a model of the signal transduction pathways involved in E2F-1-mediated apoptosis. To evaluate this model and further dissect the molecular mechanisms of E2F-1-induced apoptosis, SK-MEL-2 melanoma and HT-29 colon cancer cells will be studied. Following adenovirus-mediated gene transfer we will analyze the role of Fas/FasL interaction, JNK, p38, and ERK activation, NFKB activation, and XIAP, cIAP-1 and Mcl-1 in E2F-1-mediated apoptosis. Investigation will also be carried out using combinations of adenovirus E2F-1 and specific chemotheraeutic agents that act cooperatively with E2F-1 (adriamycin. camptothecin, temozolomide) to evaluate the mechanisms by which E2F-1 augments the apoptotic response to chemotherapy. Finally, a novel adenoviral vector expressing a truncated E2F-1 mutant that maintains apoptotic function but lacks E2F-1 transactivation function will be constructed and tested for potential enhancement of tumor death. These studies will enhance our understanding of E2F-1-mediated cell death and facilitate the design of improved treatment strategies.

描述（由申请人提供）：失败的主要原因