PROJECT SUMMARY/ABSTRACT Research in the Experimental Therapeutics (ET) program focuses on identification, development and testing of new cancer therapeutics. This is accomplished through three overlapping specific aims centered on 1) identifying potential targets and discovering therapeutics leads, 2) conducting preclinical evaluation of promising new therapeutic approaches, and 3) evaluating innovative and promising agents, combinations, and approaches to monitoring response in clinical trials. ET investigators are highly collaborative. Key scientific achievements of ET investigators over the prior funding period include identification of novel therapeutic targets in endometrial cancer and myeloma, nanoparticle based drug development, cancer immunotherapy based on toll-like receptor (TLR9) agonists, use of pharmacologic ascorbate to enhance the efficacy and reduce the toxicity of both chemotherapy and radiation therapy (in collaboration with the FRMI Program), and expansion of investigator-initiated and Phase I capabilities including trials of intralesional therapy. There are 28 full and 16 associate members of ET including laboratory-based, translational and clinical investigators spanning 13 departments across five colleges. Annual total peer-reviewed cancer direct costs in the most recent budget year was $2.7 million ($1.9 million from the NCI). Additional funding included $3.8 million for non-peer-reviewed research projects. ET members are highly collaborative having authored or co-authored 291 cancer-related peer-reviewed publications in the past five years, with 24% (n= 69) intraprogrammatic, 43% (n= 124) interprogrammatic, and 42% (n= 123) interinstitutional publications. Twenty-nine manuscripts appeared in high impact journals (Impact Factor ≥10).