PROJECT SUMMARY - Translational and Clinical Sciences Program The Translational and Clinical Sciences Program (TACS) at the USC Norris Comprehensive Cancer Center (NCCC) is co-led by John Carpten PhD, Parkash Gill MD, and Heinz-Josef Lenz MD. The Specific Aims of the TACS Program are to: 1) Discover novel targets and develop new therapeutic approaches, with emphasis on high priority cancers in our catchment area; 2) Design and conduct innovative high impact clinical trials, with emphasis on early phase and investigator-initiated trials (IITs); and 3) Develop and validate innovative diagnostic approaches and biomarkers of cancer evolution and therapeutic response. During the current grant period, the TACS Program's 54 full members have made significant advances in novel therapeutic approaches, including (but not limited to) the development of lead compounds targeting Artemis in leukemia through the NCI Experimental Therapeutics (NExT) program and the identification of a novel immunological mechanism of action of EphrinB4/EphB2 therapies towards novel combination treatments for cancer. TACS members also lead in NCI-funded clinical trials through the Experimental Therapeutics Clinical Trials Network (ETCTN) and National Clinical Trials Network (NCTN). TACS members also design and lead novel trials combining epigenetic inhibitors with immunotherapies in adult cancers with funding from Stand Up to Cancer and are national leaders in the development of circulating biomarker research including a new NCI R01 in the area of cell free DNA methylation. Through the new NCI-funded U54 Center for Health Equity, TACS members lead major efforts in translational cancer disparities research, engaging the Office of Community Outreach and Engagement and members across all five NCCC Research Programs. The exceptional progress of the TACS Program in the current period is evident in its metrics: members hold $30.4M in cancer research funding with $12.3M in peer reviewed funding, of which $6.8M is from NCI; this represents dramatic increases of 170%, 194%, and 198%, respectively, compared to the 2015 review. Members also lead or participate significantly (e.g., project or core leader) in 15 collaborative P and U grants. Of the 971 scientific papers published in this grant period, 21% are intra- programmatic, 26% are inter-programmatic, 48% are multi-institutional, and 30% are in high impact journals (IF >9). From 2015-2019, TACS members enrolled 3,641 patients to interventional trials, of which 2,983 were interventional therapeutic accruals; 57% of interventional trial accruals are underrepresented minorities. Thus, the TACS program is addressing cancer needs in our catchment area through high impact research projects in cancer disparities, through drug development and innovative trials, and faculty mentoring.