The Experimental Therapeutics (ET) Program provides an organized integrated infrastructure that enables both clinical translation of basic and population science research from Simmons Comprehensive Cancer Center (SCCC) research programs and identification of clinically relevant hypotheses for testing by SCCC basic science programs. The four program specific aims focus on therapeutic development and biomarker discovery, where members work collectively to: (1) develop molecular therapeutic sensitizers by focusing on the development of unique tumor-selective agents that enhance existing therapies, (2) target tumor microenvironment with immunotherapy by modulating the role of immune cells in tumor progression, (3) advance imaging and drug delivery by developing novel imaging and nanotechnology delivery platforms to enhance cancer diagnosis and therapy, and (4) exploit cancer vulnerabilities by leveraging synthetic lethalities as new “targeted” therapy for cancer. The ET Program brings together 78 SCCC members from six basic science and 12 clinical departments comprising 44 NCI-funded projects, including two SPOREs and 14 multi-PD/PI awards. In response to evaluative activities and strategic goals to facilitate collaborative translational research, ET recruited new senior clinical researchers; expanded translational studies and investigator-initiated clinical trials (IITs) to include most cancer types and to address the needs of the catchment area; enhanced interactions with SCCC members; integrated radiation oncology faculty into the program; and improved the infrastructure and funding for IITs. ET members participate in and lead multicenter IITs and they collaborate with pharma/biotech, which often leads to investigator-initiated trials and translational studies. Importantly, the funded SPORE programs in kidney and lung cancers and new SPORE applications in prostate and liver cancers are actively supported by ET member expertise. The ET Program has expanded therapeutic pipelines in a majority of adult and pediatric cancers. Highlighted successes include the in-house development and clinical translation of therapeutic strategies for KRAS mutant cancers, HIF2alpha-targeting for kidney cancer, antagonists against mutant estrogen receptors in breast cancers, strategies to activate the STING innate immune pathway, and clinical trials capitalizing on synergy between stereotactic radiation therapy and immune checkpoint inhibitors. Future directions include investment in preclinical models (spheroid/organoid cultures, humanized mice), precision oncology (customized panels, SCCC molecular tumor boards, recruitment of a translational leader in genomic oncology), immuno- oncology (immune profiling; novel PET tracers; systemic and organ-specific autoantibody biomarkers; expansion of the innate immunity program), disease-focused translational research programs (recruitment of leadership in breast, GI, lung, GU, neuro-oncology, hematolo...