RADIOSENSITIZATION OF PANCREATIC CANCERS THROUGH RAF-1

通过 RAF-1 对胰腺癌进行放射增敏

• 批准号: 6651745
• 负责人: ANATOLY DRITSCHILO
• 金额: $ 34.88万
• 依托单位: GEORGETOWN UNIVERSITY
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651745
• 关键词: antisense nucleic acid; athymic mouse; biological signal transduction; combination cancer therapy; drug screening /evaluation; gemcitabine; high throughput technology; human subject; human therapy evaluation; ionizing radiation; liposomes; molecular pathology; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; oligonucleotides; pancreas neoplasms; patient oriented research; protein kinase; protooncogene; radiation resistance; radiosensitizer

DESCRIPTION (provided by applicant): Raf-1 is a critical protein involved in cellular signaling pathways that enhance cell growth and survival. Inhibition of Raf-1 expression by antisense (AS) raf oligodeoxyribonucleotides (ODN) induces tumor growth arrest, DNA fragmentation in cells and sensitizes tumors to ionizing radiation. Mechanistic and preclinical data provide support for exploring the use of AS raf ODN as a radiation sensitizer for the treatment of human cancers. We have recently developed a novel liposomal encapsulated (LE) delivery system for systemic administration of AS raf ODN. Preclinical studies have shown this preparation to safely inhibit Raf-1 expression. Pancreatic cancer is an aggressive malignancy that responds poorly to chemotherapy or radiation therapy. Since 85 percent to 95 percent of pancreatic cancers show activation of the K-ras oncogene, and the raf gene product integral to the Ras/Raf/MAPK cellular signaling pathway, it follows that disruption of this pathway may provide a target for pancreatic cell radiosensitization. Phase I clinical trials of LE raf AS ODN, alone, or in combination radiation therapy are currently in progress. To test the feasibility of using LE raf AS ODN in combination with radiation therapy for the treatment of pancreatic cancer, we propose a Phase II clinical trial in patients with locally advanced disease. LE raf AS ODN will be administered with a moderate dose of radiation therapy, clinical remissions, and time to disease progression will be used as study endpoints. Molecular studies will be conducted on prostate cancer cells and on clinical specimens to provide mechanistic insight into the role of raf inhibition in radiation sensitization. This study will determine the potential for enhancing pancreatic tumor control following radiation therapy in combination with LE raf AS ODN as a radiation sensitizer.

描述(申请人提供)：RAF-1是参与细胞信号转导的关键蛋白质 促进细胞生长和存活的途径。反义RAF寡核苷酸(ODN)抑制Raf-1的表达可导致肿瘤生长停滞，细胞内DNA断裂，并使肿瘤对电离辐射增敏。机制和临床前数据为探索AS RAF ODN作为放射增敏剂治疗人类癌症提供了支持。我们最近开发了一种新的脂质体包裹(LE)递送系统，用于系统地给药AS RAF ODN。临床前研究表明，这种制剂可以安全地抑制Raf-1的表达。胰腺癌是一种对化疗或放射治疗反应不佳的侵袭性恶性肿瘤。由于85%-95%的胰腺癌存在K-ras癌基因的激活，并且RAF基因产物是Ras/Raf/MAPK细胞信号通路的组成部分，因此该通路的破坏可能为胰腺细胞的放射增敏提供靶点。LE RAF作为ODN、单独或联合放射治疗的I期临床试验目前正在进行中。为了测试LE RAF作为ODN结合放射治疗治疗胰腺癌的可行性，我们建议对局部晚期疾病患者进行II期临床试验。作为ODN的LE RAF将接受中等剂量的放射治疗，临床缓解和疾病进展时间将作为研究终点。将在前列腺癌细胞和临床标本上进行分子研究，以提供对RAF抑制在辐射增敏中的作用的机制洞察。这项研究将确定联合LE RAF AS ODN作为放射增敏剂的放射治疗后加强胰腺肿瘤控制的潜力。