RADIOSENSITIZATION OF PANCREATIC CANCERS THROUGH RAF-1

Georgetown University, Washington DC

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Abstract

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.