New approach to improve abdominopelvic radiotherapy by protecting small intestine

DESCRIPTION (provided by applicant): One third of cancer survivors in the United States have undergone abdominopelvic radiation therapy (APRT). Bowel toxicity limits the efficacy of APRT and lowers the quality of life for cancer survivors. The ultimate goal of this program is to develop new approaches to selective protection of the Gl tract from radiation reducing postradiation intestinal dysfunction and improving the lives of a large number of patients. Our proposal is focused on the improvement of therapeutic efficacy of APRT in ovarian cancer model. APRT is widely used as adjuvant therapy in ovarian cancer treatment and prolongs disease-free survival. Dose escalation improves survival but leads to severe bowel toxicity, indicating the possibility to improve survival of patients by mitigation of APRT side effects. Our preliminary studies have shown that flagellin of Salmonella and its optimized derivative delta-FL-AA' act as a powerful radioprotectants of Gl tract acting via Toll-like receptor 5-mediated activation of NF-kappa-B signaling pathway. This protection is selective for normal cells and does not affect radiosensitivity of experimental tumors. Current proposal is devoted to feasibility of this approach in mouse model of ovarian cancer. The success of this work will lay the ground for further developmental steps essential to bringing delta-FL-AA' to clinical trials.