The long-term goal of this translational research program is to improve the therapeutic ratio, i.e., to increase the complication-free cure rate, of radiotherapy for the management of various cancers. This goal will be accomplished by the development of rational strategies to enhance radiation effectiveness through modulation of emerging molecular targets and by identifying potential markers for radiation response using molecular profiles derived from tissue specimens of patients enrolled onto previously funded clinical trials. The theme of this competing renewal application, "Modulation and Prediction of Radiation Response of Cells and Tissues", therefore, aims at designing molecular-targeted approaches to overcome radiation resistance and to identify molecular predictors of normal tissue and tumor response to radiotherapy. The program consists of four research projects supported by three core components. Three projects investigate the mechanism and efficacy of tumor radiation sensitization by targeted molecular interventions, i.e., by transfer of novel genes, mda-7, by blockade/inhibition of EGFR or cyclooxygenase-2 (COX-2), or by antiangiogenic agents. The fourth project addresses molecular profiling of normal and malignant tissues to identify predictors and potential targets for radiation response. The core components consist of General Laboratory Support, DNA Microarray, and Administrative Services. Several investigators participate in more than one project and there are substantial scientific interactions among the projects. The proposed research program has grown due to the close collaboration among clinicians and basic scientists from many departments who have benefited from the expertise and resources available at the University of Texas M. D. Anderson Cancer Center. The proposed work is anticipated to have a significant impact on radiation oncology with regard to both basic radiobiology and clinical applications.