Genetic Mechanisms Program Summary The Genetic Mechanisms (GM) Program is a basic science program that focuses on cancer gene discovery, mechanisms of genome instability, and gene therapy. The scientific goals of GM are to define and understand the genetic changes that occur during cancer development, including the specific changes that drive tumor initiation, progression, and drug resistance, and to translate our basic science discoveries into preclinical pipelines. We will continue to focus on areas where we have made significant progress over the last 5 years, including studies on the discovery of DNA damage tolerance pathways that can lead to drug resistance in repair-deficient cancers, repurposing of existing drugs for cancer therapy, and adoptive immunotherapy with genome-engineered cells and viruses. These larger goals are underpinned by the following Specific Aims: 1) Identify cancer vulnerabilities, 2) Understand cancer genome evolution, and 3) Develop viral & cellular therapies. The GM Program is co-led by Masato Yamamoto, MD, PhD, a clinician-scientist whose research program focuses on oncolytic viral therapies against solid tumors and the relationship between obesity and cancer, and R. Stephanie Huang, PhD, whose research uses bioinformatics to predict and analyze the efficient repurposing of FDA-approved drugs to treat cancer vulnerabilities. GM has 56 members, representing 20 departments and 8 schools or colleges. For the last budget year, these members were supported by $16.4 million in cancer- relevant research funding (direct costs), of which $3.1 million is from the National Cancer Institute. Since 2018, Program members have published 688 papers, 18% of which resulted from intraprogrammatic collaborations, 33% from interprogrammatic collaborations, and 82% from external collaborations. The Masonic Cancer Center has provided substantial value to the program, including access to Shared Resources and the cGMP-compliant Molecular and Cellular Therapeutics production facility. Internal funding for multiple pilot studies was crucial to developing new collaborative projects, including a P01 focused on APOBEC3B. Lastly, GM has greatly benefitted from new and diverse MCC recruits. Several physician- scientists, including several underrepresented minority researchers who have a strong interest in functional genomics, have joined our Program in the past 5 years.