ABSTRACT: This proposal entitled A dual acting drug for enhancing radiotherapeutic benefit is designed to provide proof of concept evidence that the novel compound EWA001 can protect normal lung tissue from radiation-induced damage within an in vivo model without appreciably protecting neoplastic tissue. The protection of radiation induced lung toxicity from ionizing radiation and in particular, radiation induced pneumonitis and fibrosis, is an unmet need that may benefit thousands of patients considering that more than two thirds will receive radiation therapy during the course of their treatment for cancer with such complications limiting treatment or even resulting in death. In aim 1, we will examine the effect of EWA001 in tumor LLC and human tumor xenografts in vitro and in vivo in conjunction with radiation. In aim 2, we will investigate EWA001's efficacy at protecting against and mitigating radiation induced lung injury in mice. Currently, there is no drug available that would minimize radiation toxicity to normal tissue without interfering with its anti-tumor effect and this data is designed to lead to a successful phase II application where we will further develop the pre-clinical data towards an effective drug to treat radiation induced lung toxicity and pneumonitis.