PROJECT SUMMARY/ABSTRACT During the past two decades a significant body of evidence has shown that metabolic oxidation/reduction reactions represent a significant underlying mechanism contributing to promotion and progression of malignancy, as well as a therapeutic target for selectively sensitizing cancer cells to therapeutic interventions and protecting normal tissues from conventional cytotoxic therapies. Evolving in parallel has been the recognition that advanced medical imaging techniques, measuring metabolic changes in cancer versus normal tissues before and during therapy show great promise in allowing non-invasive quantitation and monitoring of fundamental differences in cancer cell metabolism to improve cancer therapy. The overarching hypothesis in the Free Radical Metabolism and Imaging (FRMI) program is that cancer cells exist in a chronic state of metabolic oxidative stress that represents a significant underlying mechanism contributing to promotion and progression of malignancy as well as a therapeutic target for sensitizing tumor cells to therapy as well as protecting against normal tissue injury. Furthermore, functional imaging techniques measuring metabolic changes in tumors versus normal tissues have shown great promise as predictors and biomarkers that can be used to improve cancer therapy. The diverse membership of this unique program includes 33 full members and five associate members representing two colleges and nine departments. These investigators work together to take full advantage of the convergence of the science in these two related disciplines for developing a mechanism based biochemical rationale for new image-guided cancer therapies and diagnostic/prognostic tools. FRMI members are highly collaborative. During the last period of support, 83% of a total of 235 cancer relevant publications were collaborative including 75 (32%) intraprogrammatic, 83 (35%) interprogrammatic and 127 (54%) interinstitutional publications including 17 in high impact (Impact Factor >10) journals. Program member cancer research was supported by $3.7 million of direct peer-reviewed funding including $2.1 million of NCI funding in the last year of CCSG support. Productive intra/interprogrammatic and interinstitutional groups are leading advances in the development of pharmacological ascorbate as an adjuvant to cancer therapy supported by a new NCI P01, superoxide dismutase mimetics for protection of normal tissues toxicities, and peptide-targeted, radionuclide-based theragnostic treatments.