Project Summary/Abstract: Targets, Modulators, and Delivery Program (TMDP) The mission of the Targets, Modulators, and Delivery Program (TMDP; formerly known as the Cancer Genes and Molecular Regulation Program) is to validate targets, develop small molecules that modulate cancer targets, and develop methods for efficient delivery of modulators to tumor cells. The TMDP is organized to promote collaboration and catalyze the translation of scientific discoveries from Fred & Pamela Buffett Cancer Center (BCC) basic research program members while providing BCC translational research programs access to validated targets, small molecule modulators, and delivery methods for clinical translation. The TMDP integrates the efforts of 18 physician-scientists (including adult and pediatric hematologist/oncologists, radiation oncologists and surgical oncologists) with expertise in clinical trial development and 23 investigators with expertise in cancer target development, medicinal chemistry, pharmacology, and nanodelivery. Together, the program members develop tools and technology to facilitate translation of basic science discoveries by the bench-to-bedside continuum within BCC research programs. Resources developed by the TMDP to support novel chemical entity (NCE) discovery/development within the TMDP and the BCC include the Synthetic and Medicinal Chemistry Resource, PROteolysis Targeting Chimera (PROTAC) synthesis and Computational Chemistry Resource. The translational research efforts of the TMDP faculty extend across the full range of malignancies that are of critical importance to the population of Nebraska, including lung cancer, ovarian cancer, multiple myeloma, lymphoma, acute leukemia, breast cancer, pancreatic cancer and medulloblastoma. The research interests of TMDP faculty are organized around three interactive themes – Target Validation, Small Molecule Modulators, Delivery Methods – that contribute to the overarching goal of bench-to-bedside research translation through intra- and inter- programmatic collaboration. These themes exemplify the specific aims of the TMDP to 1) develop conceptual and technical approaches to validate cancer targets; 2) identify and characterize target- and mechanism-specific small molecules directed at validated cancer targets; and 3) explore novel technologies for efficient delivery of small molecules or RNAi against validated cancer targets. Physician scientists within the TMDP with clinical trials expertise facilitate the translation of putative targets, chemical modulators, and delivery methods with therapeutic potential. The interactions between TMDP members, their interactions with other BCC Programs, and their inter-institutional collaborations promote impactful and translational studies. These interactions have resulted in $4.25M (direct) of cancer-relevant peer-reviewed funding to TMDP investigators, with 3.17M from the NCI. During the funding period, the TMDP investigators reported 647 cancer-relevant pub...