Nuclear Receptor, Transcription and Chromatin Biology Program

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NUCLEAR RECEPTOR, TRANSCRIPTION, AND CHROMATIN BIOLOGY (NRTBC) PROGRAM PROJECT SUMMARY The overall objective of the NRTCB program is to conduct impactful basic research and to promote rapid translation of discoveries linked to NR-dependent and epigenetic mechanisms of transcriptional regulation of carcinogenesis to the clinic to accelerate development of new preventative and therapeutic interventions. The program has 2 main themes: (1) Identification of NRs that contribute to cancer pathogenesis and progression, disclosure of their mechanisms of action, and evaluation of their potential as novel therapeutic targets, and (2) Biology and function of chromatin regulators that mediate epigenetic regulation of transcription in cancer. The program has 20 actively funded Research Members, 2 Clinical, 2 Adjunct, and one Shared Member with extensive research experience related to the 2 themes and drawn from several departments including Medicine, Molecular and Cellular Biology, Molecular and Human Genetics, and Pharmacology. The program is led by Dr. Suzanne Fuqua, a translational research expert in estrogen receptor action in breast cancer, together with 2 Co- Leaders, Dr. Cheryl Walker, an internationally recognized expert on environmental, genetic, and epigenetic factor interactions in cancer and Dr. Nicholas Mitsiades, a clinical researcher with extensive experience in oncology clinical trial design and execution in the area of NRs and prostate cancer. Members of the Program have $15.9 million (direct costs) in cancer-related research funding, of which $9.9 million is peer-reviewed and $6 million is non peer-reviewed. Peer-reviewed funding includes nearly $6.4 million in NIH support, of which $5.3 million is from the NCI. NRTCB Program members have a strong record of programmatic interactions as evidenced by 16 externally funded programmatic grants. Members continue to make outstanding research progress as evidenced by over 321 cancer-related publications over the past 5 years of which 25% and 70% involve intra- and inter- programmatic collaborations and 52% are inter-institutional. Major scientific accomplishments include novel discoveries of (1) a role of androgen receptors in breast cancer resistance to endocrine therapies, (2) a role for the NR, CAR in liver cancer, (3) a novel miRNA-regulated signaling axis required for suppression of COUP-TFII driven prostate cancer metastasis, (4) glucocorticoid receptors as novel therapeutic targets for RUNX1-ETO positive acute myeloid leukemia, (5) a role for epigenetic regulators in control of cytoskeletal dynamics, (6) a role for Warburg-associated glycolytic reprogramming in epigenetic activation of SRC-3 driven oncogenic transcriptional programs, and (7) a role for prostate cancer associated mutations in SPOP in regulation of androgen receptor turnover. Translational advances include: (1) Preclinical validation of the NR4A activator, dihydroergotamine, as a novel therapeutic drug for AML, (2) Four new investigator-initiated trials including: tamoxifen for treatment of bladder cancer; meclizine, an inverse agonist for CAR, for treatment of liver cancer; Sertraline for treatment of myelodysplastic syndrome; and racial disparities in hormonal therapy response in men with metastatic prostate cancer, and (3) Commercial development of new first-in-class therapies targeting SRC- 3 with Coactigon Inc.