OVERALL PROJECT SUMMARY Yale Cancer Center (YCC) seeks to be a leader in eliminating the burden of cancer through transformative research, with attention to the needs of all people facing this disease. We will work collaboratively to pursue this goal with a relentless focus on reducing cancer disparities, while maximizing access to care, addressing the needs of the community, ensuring equity and diversity in our workplace, and training future cancer researchers, clinicians, and leaders. For fifty years, YCC has conducted high-impact cancer research, and today a deep culture of collaboration unites 305 basic, translational, population, and clinical scientists focused on cancer. YCC members conduct research to understand and prevent cancer, detect cancer early, and treat cancer more effectively. Based on the recognition that many individuals do not receive the best care, YCC will mount a major effort to understand the basis for disparities in cancer care and outcomes and to use this knowledge to combat these disparities through enhanced research in our Catchment Area in partnership with our local community. This effort will be reinforced by a plan to increase the diversity of the YCC staff through directed recruitments and promotions and through reinvigorated training and education efforts. Six Research Programs are the heart of YCC research, resulting in 2422 publications during the current project period, 30% in high-impact journals. The Research Programs are led by basic, translational, clinical, and population scientists working in partnership to foster transdisciplinary research. YCC supports and manages Shared Resources that provide exceptional state-of-the-art technologies to enable groundbreaking discoveries. YCC investigators conduct a growing number of innovative clinical trials that translate laboratory discoveries into the clinic and incorporate novel designs and biomarker assessments to optimize patient selection, define treatment resistance, and inform new therapeutic approaches. This work relies on close partnerships between laboratory and clinical researchers. Clinical trials led by YCC investigators during the current project period led to breakthroughs in cancer treatment including five FDA approvals. Since 2018, overall cancer funding (direct costs) increased 6.6% to $94.9M, including a 9% increase in NCI funding to $26.5M. YCC holds three NCI SPORE grants, numerous U-type and other multi-investigator grants, and a leadership role in a SU2C Dream Team award. $1.9M in CCSG internal grant funding distributed 2016-2021 resulted in $23.2M in external funds that could be directly linked back to these internal grants, a 12.3-fold return on investment. Importantly, during the current project period, the YCC leveraged these CCSG funds with philanthropic and other sources to generate a total of $10.2M distributed as peer reviewed internal grants for cancer research. Over the next five years, YCC will continue to develop initiatives and re...