PROJECT SUMMARY/ABSTRACT The Cancer Cell Biology Program (CCB) personalizes cancer therapy by i) elucidating signaling and metabolic networks controlling key cancer cell functions, ii) employing cutting-edge chemical biology and biologics to target rate-limiting pathways in cancer, and iii) translating these insights to the clinic as improved therapies or biomarkers that more accurately predict patient response. We address key cancer problems in our catchment area, facilitated by biannual meetings with the Community Outreach and Engagement Core and our designated CCB Liaison. Particular emphasis is placed on melanoma, and lung, pancreas, triple negative breast, and prostate cancer, reflecting major catchment area burdens and disparities. Research is organized around three complementary thematic aims: Aim 1: Identify regulatory mechanisms for key cancer-relevant genes that confer selective dependencies in human tumors, Aim 2: Delineate how metabolism is reprogrammed in cancer and discover targetable metabolic vulnerabilities, and Aim 3: Use structural, chemical, protein engineering, and pharmacologic approaches to target cancer cell dependencies for therapeutic benefit. CCB is under tripartite leadership by Richard Possemato, PhD (Basic), Alec Kimmelman, MD, PhD (Translational), and Vamsidhar Velcheit, MD (Clinical). Our 53 Members and 14 Associate Members hail from 12 Departments at NYU Grossman School of Medicine, the NYU Department of Chemistry, and the NYU College of Dentistry. CCB Members have $24.2M in cancer-related funding (41% increase), including $8.3M in NCI grants (32% increase). Members are highly productive and collaborative, publishing 806 peer-reviewed papers in high-impact journals (36% with IF>10, 19% IF>15), with 16% intra-programmatic, 36% inter-programmatic, and 42% inter-institutional publications during the current funding period. We filed 41 patents (19 licensed), had 26 patents issued (7 licensed), and created 5 biotechnology companies. Most importantly, CCB members made seminal findings with clinical impact, including identifying novel signaling networks or metabolic dependencies. CCB houses the Perlmutter Cancer Center (PCC) Biologics Initiative, which produced antibodies licensed to BioPharma and in clinical trials or late-stage pre-clinical development. Multiple CCB discoveries have advanced along the translational pipeline, including into clinical trials that are, or will soon be, open at PCC. CCB clinical investigators also led 15 IITs, 4 ISTs, and multi-site trials and totaled 3,548 accruals, a dramatic increase driven by recruitment of additional clinical trialists.