PROJECT SUMMARY/ABSTRACT The Markey Cancer Center’s (MCC) Translational Oncology (TO) Research Program is scientifically focused on identifying novel targets, discovering new anticancer agents and devices, and leading catchment-relevant clinical trials to decrease cancer incidence and mortality in Kentucky and the nation. The overarching theme of the TO Program is to use precision medicine to enhance patient outcomes through three Specific Aims: 1) Identify and validate mechanistic targets of cancer, 2) Discover, re-design and develop new anticancer agents and devices, and 3) Develop and lead biomarker directed, catchment-relevant clinical trials. Currently, 33 ongoing translational studies are evaluating molecular targets and mediators of cancer. Since 2018, 38 new drugs, novel combinations and repurposed anticancer agents and devices have been developed, with a focus on identified mutations and phenotypes as informed by COE catchment area data. TO is a cross-disciplinary program with 67 investigators from four colleges and 16 departments producing research awards of approximately $10M in annual direct costs, a 68% increase from 2017, including $1.8M from the NCI and $3.4M from other NIH agencies. Members have published 613 manuscripts (2018 to 2022), of which 148 (24%) are inter-programmatic, 169 (28%) are intra-programmatic, 344 (56%) are inter-institutional, and 13% of which have an impact factor >10. TO members lead 26 new therapeutic interventional investigator-initiated trials (IITs), a 53% increase since the previous funding period (17 IITs, 2013-2017). These IITs have enrolled 870 patients (2018-2022), a 111% increase in IIT accruals (413 patients, 2013-2017), with 52% of participants from Appalachia. In addition, TO investigators enrolled 12,689 individuals to the program’s interventional and non-interventional trials, compared to 8,571 from 2013-2017, a 48% increase. TO Program members are international leaders in target discovery and validation, have national and international collaborations and hold leadership roles in the National Cancer Institute’s Experimental Therapeutics Clinical Trials Network, the Oncology Research Information Exchange Network and Onco-Array Networks, and the MCC-led Global Cancer Consortium. The TO Program fosters continuous collaboration among MCC program members to inform and advance MCC basic science into the clinic. A notable example is translating early identification of the biomarker FASN to an ongoing colorectal cancer trial. The TO Program has a cohesive and collaborative team focused on translating MCC scientific discoveries into safe and effective anticancer treatments with a demonstrated depth and breadth of impact in MCC’s catchment area, nationally and internationally.