Nuclear Receptor, Transcription and Chromatin Biology Program

核受体、转运和染色质生物学（NRTBC） 项目摘要 NRTCB计划的总体目标是进行有影响力的基础研究，并促进快速发展。 翻译的发现与NR依赖和表观遗传机制的转录调控， 将致癌作用应用于临床，以加速开发新的预防和治疗干预措施。的 该项目有两个主要主题：（1）鉴定有助于癌症发病和进展的NR， 公开其作用机制，并评价其作为新治疗靶点的潜力，以及（2） 在癌症中介导转录表观遗传调节的染色质调节因子的生物学和功能。的 该计划有20个积极资助的研究成员，2个临床，2个辅助，和一个共享成员， 与这两个主题相关的广泛研究经验，来自多个部门，包括医学， 分子和细胞生物学，分子和人类遗传学，药理学。该计划由博士领导。 Suzanne Fuqua是乳腺癌雌激素受体作用的转化研究专家，她与2 Co- 领导人，谢丽尔步行者博士，一个国际公认的专家对环境，遗传和表观遗传因素 癌症的相互作用和Nicholas Mitsiades博士，一位在肿瘤学方面具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执行。该计划的成员有15.9美元 2010年，美国癌症相关研究经费为1000万美元（直接费用），其中990万美元用于同行评审，600万美元用于 未经同行评审同行评审的资金包括近640万美元的NIH支持，其中530万美元是 从国家癌症研究所NRTCB计划成员在计划互动方面有着良好的记录， 外部供资的方案赠款。成员继续取得突出的研究进展， 在过去5年中，超过321篇癌症相关出版物，其中25%和70%涉及内部和内部， 方案合作，52%是机构间合作。主要科学成就包括： 发现（1）雄激素受体在乳腺癌对内分泌疗法的抵抗中的作用，（2） 肝癌中的NR、CAR，（3）抑制COUP-TFII所需的新的miRNA调节的信号轴 驱动前列腺癌转移，（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细胞骨架动力学控制中的作用，（6）表观遗传调节因子在细胞骨架动力学控制中的作用， 对于Warburg相关糖酵解重编程在SRC-3驱动的致癌基因的表观遗传激活中的作用， 转录程序，和（7）前列腺癌相关的SPOP突变在调节 雄激素受体转换转化进展包括：（1）NR4A激活剂的临床前验证， 双氢麦角胺作为AML的新型治疗药物，（2）四项新的兴奋剂启动的试验，包括： 美克洛嗪，CAR的反向激动剂，用于治疗肝癌; 舍曲林治疗骨髓增生异常综合征及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的新型一流疗法的商业开发- 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.