PROJECT SUMMARY MOLECULAR MEDICINE PROGRAM The overarching goal of the Molecular Medicine (MM) Program is to integrate systems biology, drug discovery, and precision medicine approaches to develop, validate and deliver new therapeutic strategies and agents, and to drive landmark trials that improve standard-of-care for patients in our catchment area and beyond. Key priorities of MM are to: 1) identify and validate key effectors and biomarkers of circuits that drive cancer progression, metastasis, and therapy resistance; 2) develop new molecular probes that will facilitate mechanistic understanding of the roles of priority targets in tumorigenesis; 3) optimize drug-like properties of targeted agents through medicinal chemistry, for testing in clinical trials; and 4) conduct impactful clinical trials that lead to changes in standard of care. To accomplish these goals, MM research is organized into three Specific Aims: Aim 1: To identify and validate pathways and targets of cancer metastases and therapy resistance. Aim 2: To define mechanisms of action and optimize existing drugs and lead compounds. Aim 3: To design and implement therapeutic trials with a precision medicine approach. MM is comprised of 55 basic and clinical researchers who have formed multidisciplinary teams that create unique opportunities for translational research focused on bench-to-bedside medicine. Further, in a feed-forward fashion, findings coming from clinical trials inform important new research at the bench, to refine strategies and targeted agents, and to develop predictive biomarkers of diagnosis, prognosis, and response. This robust cyclic pipeline of research and trials has been driven by the recruitment of twelve new Members to the MM Program, which has a healthy balance of 15 Assistant, 15 Associate, and 25 Senior Members, as well as by investments in key target areas that address the Specific Aims and key catchment area priorities identified by Moffitt’s Office of Community Outreach, Engagement, and Equity. The MM Program currently holds $35.2 M in total funding, including $8.9M in peer-reviewed funding and $26.3M in non-peer-reviewed funding. MM members published 1,302 articles, with 323 (25%) intra-programmatic publications, 412 (32%) inter-programmatic publications, and with 272 high impact articles (impact factor >10). Importantly, MM accrued 3,926 patients to interventional clinical trials, including 2,333 to investigator-initiated trials. Notably, MM research on melanoma, lung cancer, and cancers in elderly patients have made a significant impact on the cancer burden and at-risk populations in our catchment area and, importantly, MM clinical trials have resulted in FDA approvals and changes in National Comprehensive Cancer Network (NCCN) guidelines. Future priorities of the MM Program are to: 1) combine unbiased cell-based phenotypic screening with chemistry and proteomics to simultaneously identify target and chemical leads; 2) fully integrate bulk and singl...