Nuclear Receptor, Transcription and Chromatin Biology Program

核受体、转录和染色质生物学(NRTBC)计划 项目总结 NRTCB计划的总体目标是进行有影响力的基础研究，并促进快速 与NR依赖和表观遗传学转录调控机制相关的发现的翻译 将癌变推向临床，加速发展新的预防和治疗干预措施。这个 该计划有两个主要主题：(1)识别有助于癌症发生和发展的NRs， 披露它们的作用机制，并评估它们作为新的治疗靶点的潜力；以及(2) 在癌症中介导转录表观遗传调控的染色质调节剂的生物学和功能。这个 该计划有20个积极资助的研究成员、2个临床成员、2个附属成员和1个共享成员 与这两个主题相关的广泛研究经验，来自包括医学在内的几个部门， 分子和细胞生物学、分子和人类遗传学以及药理学。该项目由Dr。 Suzanne Fuqua，乳腺癌中雌激素受体作用的翻译研究专家，和2个Co- 领导，谢丽尔·沃克博士，国际公认的环境、遗传和表观遗传因素专家 癌症中的相互作用和尼古拉斯·米西亚兹博士，一位在肿瘤学方面拥有丰富经验的临床研究人员 NRS和前列腺癌领域的临床试验设计和实施。该计划的成员有15.9美元 百万美元(直接成本)与癌症相关的研究资金，其中990万美元是同行评审，600万美元是 未经同行评审。同行审查的资金包括近640万美元的NIH支持，其中530万美元是 来自国家情报局。NRTCB计划成员有很强的程序性互动记录，16个就是证明 外部资助的方案赠款。成员们继续取得显著的研究进展，这是有目共睹的 在过去的5年里，超过321种与癌症相关的出版物，其中25%和70%涉及癌症内部和外部 方案协作和52%是机构间协作。主要科学成就包括小说 发现(1)雄激素受体在乳腺癌内分泌治疗抵抗中的作用，(2)雄激素受体在 肝癌中的NR，CAR，(3)抑制COUP-TFII所需的新的miRNA调节的信号轴 促进前列腺癌转移；(4)糖皮质激素受体作为RUNX1-ETO的新治疗靶点 阳性急性髓系白血病，(5)表观遗传调节因子在控制细胞骨架动力学中的作用，(6)作用 在SRC-3驱动的致癌基因的表观遗传激活中进行Warburg相关的糖酵解重编程 转录程序，以及(7)前列腺癌相关SPOP突变在调节 雄激素受体周转。翻译方面的进展包括：(1)NR4A激活剂的临床前验证， 二氢麦角胺作为一种治疗急性髓细胞白血病的新型药物，(2)四项由研究人员发起的新试验，包括： 他莫昔芬治疗膀胱癌；美克利嗪，CAR反向激动剂，治疗肝癌； 舍曲林治疗骨髓增生异常综合征；男性激素治疗反应的种族差异 转移性前列腺癌，以及(3)针对SRC的一流新疗法的商业开发-- 3与Coactigon Inc.

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.