Novel Anticancer Agents to Promote the Efficacy of Contemporary of GRID Radiation Therapy for the Treatment of Lung Cancer

The goal of this project is to translate basic biologic knowledge into a practical application for enhancing the efficacy of radiation therapy for the treatment of lung cancer. Lung cancer represents one of the great challenges of oncology. Radiation, surgery and chemotherapy alone or in combination have been employed in attempts to improve treatment outcome. Yet over the past 30 years the five-year survival ofIung cancer patients has only improved modestly. Advances in the understanding of molecular pathways of cancer have progresses to the point that new biological targets for therapy and potential therapeutic agents have been identified. Proteosome inhibitors and COX-2 inhibitors are prominent candidates for new therapeutic agents that may enhance radiation response of tumors. Both proteosome inhibitors and COX-2 inhibitors are associated with tumor apoptosis and limit tumor angiogenesis. Cell cultures studies demonstrate both these agents preferentially increase tumor cell sensitivity to radiation compared to non-tumor cells. Thus, combining proteosome inhibitors and/or COX-2 inhibitors with radiation is expected to enhance the tumor control without enhancing normal tissue toxicity. GRID radiation is a method of delivering spatially fractionated radiation using multiple pencil beams with unirradiated segments between. The advantage of delivering spatially fractionated radiation is the ability to kill large numbers of tumor cells while leaving islands of normal unirradiated tissue for recovery. The killing of unirradiated tumor is thought to be mediated by the by-stander effect. In-vitro studies have found increased cytokine production and apoptosis in cells neighboring the irradiated field after GRID treatment. Combining biologic agents that preferentially sensitize tumor to the process of apoptosis may enhance the efficacy of radiation treatment, particularly with GRID therapy through its known association with apoptosis and the by-stander-effect.