ABSTRACT, Experimental and Developmental Therapeutics (EDT) Research Program The mission of the EDT Program is to facilitate and translate mechanism-based research to improve therapies for cancer. Work toward this mission is conducted under two themes: Theme 1, Elucidation of fundamental biology to identify new cancer-selective targets for therapy, and Theme 2, Translation of mechanism-based therapies to the clinic. Theme 1 encompasses basic discovery research in two aims to: 1) probe cancer biology to identify new cancer-selective targets; and 2) identify lead compounds for therapeutic proof of concept studies. Theme 2 links translational and clinical aims to: 3) conduct IND-enabling preclinical studies of new antitumor agents; and 4) conduct mechanism-based clinical and biomarker-driven trials. To support these aims, the EDT Program established a cost-effective collaborative platform, Cancer Drug Discovery and Development Accelerator, that empowers a robust and sustainable drug discovery and development portfolio providing expertise for projects from target identification to clinical proof of concept for all programs at IUSCCC. The EDT Program serves as a central hub for cancer therapeutic development to coordinate clinical testing of novel therapies that come from our basic science and translational laboratories and those of our collaborators. The Program is co-led by Pollok and Opyrchal, who have complementary expertise in basic and clinical cancer research. The Program has 49 Full members: 28 basic science and 21 clinical investigators from 18 Departments, who focus on development of novel therapeutic strategies and evaluation of these approaches in investigator-initiated trials (IITs). The Program currently has $21M in direct funding, including $10.6M in peer- reviewed funding (a 31% increase from $8.1M in the previous cycle) with $5.16M from the NCI, $3.9M from other NIH institutes, and $1.6M from other sources. The EDT Program enrolled 1,927 patients in therapeutic trials from 2018 to 2023 (385.4/year), 71% of which were from IITs, national cooperative groups, or external peer-reviewed studies with only 29% industry-sponsored (overall 26% decrease but 27% increase in institutional IIT accruals). The End Lung Cancer Now program is an example of EDT members working with IUSCCC Office of Community Outreach and Engagement and community advocates to increase access to clinical trials for underserved communities and obtain feedback on highest needs from the patients in our catchment area. EDT members are highly collaborative with 47% of publications in this grant period being inter-programmatic, 51% inter-institutional, and 25% intra-programmatic. Members contributed to 703 publications, including 154 in high-impact journals (22%; 90% increase from prior period). In alignment with the IUSCCC Strategic Plan, EDT has benefited greatly from strong collaborative partnerships with the other Programs (HHM, TMM, and CPC) complemented by consistent out...