ABSTRACT The mission of the Cancer Cell Biology Program (CCB) is to fulfill the promise of personalized cancer therapy by elucidating the critical signaling and metabolic networks controlling cancer cell properties, employing cutting-edge chemical biology to more effectively target rate-limiting pathways in cancer, and translating these insights to the clinic, via improved therapies or better biomarkers. To address these challenges, CCB has recruited multiple new, world-class investigators who critically complement existing areas of excellence and promote high quality, collaborative research. Co-led by Alec Kimmelman MD, PhD, recently recruited as Chair of Radiation Oncology, and Michele Pagano MD, Chair of Biochemistry and Molecular Pharmacology, HHMI investigator, and Director of the former Growth Control Program at PCC, CCB is a multi-disciplinary team of 49 members and 3 associate Members from 15 departments at NYU School of Medicine (NYUSoM) and the NYU Department of Chemistry, who perform basic, translational, and clinical research. This highly restructured program retains select members from the former Growth Control and Stem Cell programs, incorporates several members from the former Breast and GU programs, and has a substantially re-focused agenda. Research is now organized around three complementary thematic aims: Aim 1) To identify regulatory mechanisms for key cancer-relevant genes that confer selective dependencies in human tumors; Aim 2) To delineate how metabolism is reprogrammed in cancer and discover new metabolic vulnerabilities; Aim 3) To use structural, chemical, protein engineering and pharmacological approaches to target cancer cell dependencies for therapeutic benefit. Program members have >$17.2M in cancer-related funding, including $6.3M in NCI grants, $8.1M in other peer-reviewed funding, and $2.8M in non-peer reviewed support. Members are highly productive and collaborative. During this funding period, we published 604 papers, many in high-impact journals, with 11% intra-programmatic, 32% inter-programmatic and 27% inter-institutional (NCI-CC) publications. CCB contributed key new insights into our basic understanding of signaling and metabolic vulnerabilities in genetically defined cancer subtypes, uncovered new molecular targets, and designed, developed and/or tested new therapies in investigator-initiated trials (IITs) and elucidated their mechanism of action or resistance. CCB promotes the PCC mission by: (1) producing innovative, high-impact science that reveals new therapeutic targets in cancer cells and their microenvironment; (2) discovering new cancer drug molecule candidates; (3) accruing patients to high-impact, high-content clinical trials; and (4) developing sophisticated technologies beyond the reach of individual investigators via the new PCC Biologics Initiative and Developing Metabolomics shared resource. There is a particular focus on cancers impacting our catchment area (l...