PROJECT SUMMARY/ABSTRACT The Clinical and Experimental Therapeutics (CET) Program is a cohesive, integrated group of 74 members representing 10 different Departments. The overall goal of the Program is to foster interactions between basic and clinical investigators with a focus on design and execution of innovative immunologic and molecular targeting driven trials at all phases of drug development, with the ultimate objective of developing personalized and effective cancer therapies. As the coordinating arm of clinical/translational research within the University of Chicago Comprehensive Cancer Center (UCCCC), the CET program interfaces with all other programs to seamlessly integrate fundamental cancer research with clinical research and care objectives. The program co-leaders include Chin-Tu Chen, PhD, a laboratory-based scientist with experience in imaging biomarkers and theranostics; Wendy Stock, MD, MA, a medical oncologist with expertise in clinical trials and clinical drug development for hematologic malignancies; and Russell Szmulewitz, MD, a medical oncologist with expertise in therapeutic development and biomarkers for genitourinary malignancies. Mark Applebaum, MD, a pediatric oncologist with expertise in therapeutics and biomarkers for pediatric solid tumors contributes as an Assistant Leader. The CET prioritizes and has led investigator-initiated studies across the different tumor types, especially those with a high mortality, prevalence, and population disparity in the UCCCC catchment area. CET investigators led 86 investigator- initiated interventional trials (IITs) and sponsored 45 Investigational New Drugs/Devices during this reporting period. CET investigators have contributed to important advances in anticancer target validation, predictive and prognostic biomarkers, and insights into overcoming resistance mechanisms through IITs and correlative science. CET members have led practice-changing, multi-institutional clinical trials through the NCTN leadership and multi-center IITs. CET led/co-led UCCCC inter-programmatic working groups, seminars and CET-sponsored meetings form the intellectual framework for translation of mechanistic insights that lead to these innovative trials. The specific scientific aims of the CET Program are to: (1) develop and advance innovative therapeutic drug development and practice-changing clinical trials; (2) test strategies to optimize drug utilization and develop innovative biomarkers that enhance therapeutic safety, efficacy, and personalization; (3) elucidate and target mechanisms of drug resistance to enhance precision therapeutics; and (4) train the next generation of leaders in clinical and translational research through formal mentoring and career development efforts. Program members are supported by $21.3M in total funding (DC), with $4.9M in peer-reviewed funding ($3.2M from NCI), and $16.4M in non-peer-reviewed support. During 2018–2022, Program members authored 1,623 peer-reviewed publicat...