CANCER CELL BIOLOGY PROGRAM: PROJECT SUMMARY The Cancer Cell Biology Program (CCB) is an integrative, collaborative, and clinically meaningful program that represents a strategic evolution of the Lombardi Comprehensive Cancer Center (LCCC)’s prior Molecular Oncology Program, strengthened during the current project period by 4 Members of the former Breast Cancer Program, 5 from the former Experimental Therapeutics Program and by 12 new recruits. The overarching goal of CCB is to identify how defects in biological pathways cause cancer and thus expose molecular vulnerabilities that can be exploited for therapy. The CCB achieves this goal through a focus on two Specific Aims: (1) understand therapeutic vulnerabilities within cancer-related genetic, epigenetic, and DNA damage response mechanisms; and (2) elucidate druggable steps within cancer signal transduction networks. These Specific Aims cut across a spectrum of intrinsic cancer biology, emphasizing the strengths of LCCC investigators. CCB promotes intra- and inter-programmatic collaboration to address the Aims, with the ultimate goal of transformative basic science with an eye towards clinical translation. Members have made internationally recognized and paradigm-changing findings using small molecule and repurposed drug development, with direct impact for patients with treatment naïve and resistant cancers. CCB Members have demonstrated considerable entrepreneurial activity, generating and patenting intellectual property and founding their own biotechnology companies. The strategic recruitment of 12 new investigators to CCB has stimulated an infusion of new energy, depth, and breadth in each Aim; resulting in the formation of new initiatives and collaborations throughout LCCC, including targeting additional cancers and research areas that have potential for disproportionate impact on communities represented in our catchment area. Through these collaborative efforts and Aims, CCB will make impactful contributions to our understanding of cancer biology and ultimately improvement of clinical care during the next project period. CCB is home to 37 Members, encompassing 11 departments across the LCCC consortium. CCB Members possess a total of $5.7M in cancer-focused, peer-reviewed funding (Annual Direct Costs; ADC), of which $3.8M (66%) is from the NCI, $1.1M (20%) from other NIH sources, and $0.8M (14%) from other peer-reviewed funding agencies. During the current project period, CCB Members authored a total of 319 cancer-relevant publications, of which 58 (18%) were intra-programmatic, 98 (31%) were inter- programmatic, and 29% were in high impact journals (IF > 10). CCB Program members have been involved in the activation of 16 new Investigator-initiated trials (IITs; 9 therapeutic, 2 interventional non-therapeutic, 5 non- interventional) resulting in a total of 20 active IITs with 280 accruals (108 therapeutic, 131 interventional non- therapeutic, 41 non-interventional) during the project period...