PROJECT SUMMARY: TRANSLATIONAL AND CLINICAL ONCOLOGY RESEARCH PROGRAM The Sylvester Comprehensive Cancer Center (Sylvester) Translational and Clinical Oncology (TCO) Research Program (RP), established in July 2022, is led by C. Ola Landgren, MD, PhD, and Jaime R. Merchan, MD, MMSc, and is composed of 39 members representing 14 departments. TCO’s goals are to advance clinical and translational investigations leading to scientific discoveries and improved patient outcomes. In accordance with Sylvester’s 2019-2023 Strategic Plan, the Center established TCO to drive collaborative scientific efforts across the translational research continuum, enabling discoveries made in the other RPs to rapidly enter the clinical setting and develop and test novel strategies to improve cancer therapies, overcome therapeutic resistance, and implement more effective precision medicine approaches. Taking advantage of TCO members’ expertise in translational research, computational oncology, precision medicine, and the development of investigator-initiated studies, TCO has two specific aims 1) identify and characterize novel targets, molecular signatures, and biomarkers, to optimize clinical prediction, prognosis, and support new therapeutic approaches; and 2) leverage discoveries made in TCO and other RPs to develop precision medicine-, epigenetic-, and immunotherapy-based strategies to improve treatment outcomes. The availability of numerous, excellent Sylvester Shared Resources facilitates multidimensional TCO research. TCO currently has $4.9M in direct peer-reviewed funding, including $2.1M from the NCI, and $1.5M from 16 MPI grants. During the current reporting period (6/1/2018-5/31/23), TCO members published 599 peer-reviewed cancer- relevant papers: 21% were intra-programmatic, 33% were inter-programmatic, 69% involved collaboration with external institutions, and 58% included investigators from other NCI-designated cancer centers. Notably, 40% of TCO publications had an impact factor ≥10, demonstrating the quality of the studies and their recognition by the scientific community. For example, collaborative TCO research provided insights into the 1) mechanisms of resistance to non-covalent Bruton Tyrosine Kinase inhibitors in patients with chronic lymphocytic leukemia; 2) the role of LMO2 on synthetic lethality to PARP inhibition in diffuse large B cell lymphomas 3) the role of STING signaling in allogeneic stem cell transplant-induced GVHD; 4) identification of a novel role for neutrophil-derived TNF in sustaining immunosuppression and stromal inflammation in pancreatic cancer; 5) promising activity of the VEGF receptor tyrosine-kinase inhibitor, axitinib plus pembrolizumab, in patients with sarcoma (especially alveolar soft-part sarcoma); and 6) intensification of salvage radiotherapy combined with short-term androgen deprivation therapy to improve outcomes in prostate cancer patients with biochemical recurrence after prostatectomy. TCO plays a critical role in S...