CANCER GENETICS AND METABOLISM (CGM) PROGRAM: PROJECT SUMMARY Recent discoveries have uncovered an intimate interplay between genetics and metabolism in cancer. The finding that isocitrate dehydrogenase mutations alter metabolism by producing an onco-metabolite that results in changes of the epigenome and leads to cancer elegantly illustrates this dynamic. Targeting the mitochondrial tricarboxylic acid cycle by inhibiting the ketoglutarate dehydrogenase and pyruvate dehydrogenase complexes is another example. These advances have formed the scientific basis for the formation of a Cancer Genetics and Metabolism (CGM) Program at the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC). The CGM Program seeks to make significant impacts through highly collaborative and integrated projects to: (1) characterize key genetic/epigenetic/metabolic events underlying tumor initiation and progression and response to therapy in the major cancer types and key health disparities of the WFBCCC catchment area; (2) develop and strengthen clinical trials targeting specific genetic defects and metabolic intervention points associated with cancer; and (3) identify biomarkers to guide precision treatment. Although WFBCCC has had a strong emphasis in cancer genetics and metabolism research for the past decade, the CGM Program was not formally organized until 2018 in response to recommendations by the WFBCCC External Advisory Board. The CGM Program now boasts 30 investigators and is co-led by two well-established scientists with distinct research expertise who have collaboratively built a highly synergistic Program – Mikhail Nikiforov, PhD, a translational scientist pioneering significant discoveries in understanding metabolic processes governing progression and drug resistance of melanoma and multiple myeloma, and Timothy Pardee, MD, PhD, a physician-scientist with a track record in elucidating the role of metabolism in resistance to therapies for acute myeloid leukemia. The CGM Program’s total peer-reviewed, direct funding base is $4.4M. Although the CGM Program was formally established only in 2018, this highly collaborative group of investigators has authored since 2016 a total of 212 cancer-focused research publications, of which 78 (37%) were intra-programmatic, 70 (33%) were inter-programmatic, and 154 (73%) represented inter-institutional collaborations. More than 37 (17%) of these publications involved seminal discoveries and translational breakthroughs published in top-tier journals such as Cell, Cancer Cell, Lancet Oncology, Journal of Clinical Oncology, Annals of Oncology, Cell Metabolism, Nature Communications, Nucleic Acids Research, Journal of Clinical Investigation, Leukemia, and Clinical Cancer Research. In 2020, the CGM Program conducted more than 82 clinical research studies, and even during the COVID-19 pandemic, a total of 235 patients were accrued to these studies.