PROJECT SUMMARY – Genomic and Epigenomic Regulation (GER) Program The Genomic and Epigenomic Regulation (GER) Program is a basic science program with an overarching goal of discovering basic mechanisms of genomic and epigenomic regulation involved in growth and behavior of normal and cancer cells, and translating basic findings into cancer detection, prognosis and treatment in collaboration with other NCCC Programs. GER is led by Michael Stallcup PhD, who has made breakthrough discoveries in steroid hormone signaling and transcriptional regulation, and Yali Dou PhD, renowned for translation of epigenetic discoveries into novel inhibitors. Aligned with the NCCC Strategic Plan priorities focused on multi-modal biomarkers of cancer evolution and translational drug development research, the Program's Specific Aims are to: 1) Define the genomic, epigenomic, and transcriptomic features that are distinct in cancer cells relative to normal cells, and 2) Characterize regulatory mechanisms and signaling pathways responsible for cancer phenotypes to identify and validate novel potential therapeutic targets. In the current grant period, GER members made major discoveries of critical genes and pathways, leveraging the new systematic process at identifying and prioritizing potential targets to advance in a go-no-go pipeline under the new Center for Cancer Drug Development at NCCC. Signature achievements include: 1) identifying antiviral gene expression as a marker of response to DNA methylation inhibitors in leukemia; 2) creating novel bioinformatics pipelines that define tumor-specific enhancer elements, linked transcription factors, and target genes as drivers of breast and prostate cancer; 3) identifying mechanisms by which GRP78 and HSP90α escape to the cancer cell surface and drive cell survival, and demonstrating that antibodies against GRP78 and HSP90α have anti-tumor effects in animal models of various cancers; 4) establishing small molecule modulators of transcriptional regulation of the cellular circadian clock as new potential therapeutic agents; and 5) identifying a new inhibitor of a histone kinase that eliminates multiple types of cancer cells. With support from NCCC, GER fosters member interactions and drives novel collaborations through weekly and annual Program meetings, junior member mentoring, cancer-focused PhD programs, and participation in NCCC-organized Disease Research Affinity Groups and the Targets to Therapies Steering Committee. GER has 40 full members who hold $12.1M in total cancer research funding (direct costs), of which $9.9M is peer reviewed and $3.5M is from NCI, representing significant increases of 114%, 94%, and 134%, respectively since the 2015 review. During the current grant period, members published 244 cancer-relevant publications, of which 27% are intra-programmatic, 28% are inter-programmatic, and 31% are high impact (IF >9). GER leaders promote a sharp focus on catchment area cancer burdens including acute lymphobl...