Nuclear Receptor, Transcription and Chromatin Biology Program

核受体、转录和染色质生物学项目

• 批准号: 10674560
• 负责人: Suzanne AW Fuqua
• 金额: $ 3.26万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674560
• 关键词: Acceleration; Acute Myelocytic Leukemia; Address; Agonist; Androgen Receptor; Area; Basic Science; Biology; Cancer Center; Cancer Center Support Grant; Cancer Model; Cancer Prevention Intervention; Chromatin; Clinic; Clinical; Clinical Trials Design; Clinical assessments; Collaborations; Cytoskeleton; Defect; Dependence; Development; Direct Costs; Disclosure; Disease; Dysmyelopoietic Syndromes; Epigenetic Process; Estrogen Receptors; Evaluation; Funding; Genetic; Genetic Transcription; Glucocorticoid Receptor; Goals; Grant; Human; Human Genetics; International; Link; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; Medicine; Metastatic Prostate Cancer; MicroRNAs; Molecular Genetics; Molecular Target; Molecular and Cellular Biology; Mutation; Names; Nuclear Receptors; Oncogenic; Pathogenesis; Peer Review; Pharmaceutical Preparations; Pharmacology; Preclinical Testing; Prognostic Marker; Publications; RUNX1 gene; Regulation; Research; Research Personnel; Resistance; Role; Scientific Advances and Accomplishments; Sertraline; Signal Transduction; Tamoxifen; Therapeutic; Therapeutic Intervention; Training; Transcriptional Regulation; Translational Research; Translations; United States National Institutes of Health; Validation; apoAI regulatory protein-1; cancer cell; cancer clinical trial; carcinogenesis; college; epigenetic regulation; experience; hormone therapy; insight; inter-institutional; investigator-initiated trial; malignant breast neoplasm; member; men; new therapeutic target; novel; novel therapeutics; patient derived xenograft model; pre-clinical; preventive intervention; programs; prostate cancer metastasis; racial disparity; small molecule; targeted treatment; treatment response; tumorigenesis

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.

核受体、转录和染色质生物学 (NRTBC) 计划 项目概要 NRTCB 计划的总体目标是开展有影响力的基础研究并促进快速发展 与 NR 依赖性和表观遗传转录调控机制相关的发现的翻译 将致癌作用推向临床，以加速开发新的预防和治疗干预措施。这 计划有 2 个主题：(1) 鉴定有助于癌症发病机制和进展的 NR， 披露其作用机制，并评估其作为新治疗靶点的潜力，以及（2） 介导癌症转录表观遗传调控的染色质调节因子的生物学和功能。这 该计划有 20 名积极资助的研究成员、2 名临床成员、2 名兼职成员和 1 名共享成员 与这两个主题相关的丰富研究经验来自多个部门，包括医学、 分子和细胞生物学、分子和人类遗传学以及药理学。该计划由博士领导。 Suzanne Fuqua，一位乳腺癌雌激素受体作用的转化研究专家，与 2 位同事一起 领导者：Cheryl Walker 博士，国际公认的环境、遗传和表观遗传因素专家 癌症和拥有丰富肿瘤学经验的临床研究员 Nicholas Mitsiades 博士之间的相互作用 NR 和前列腺癌领域的临床试验设计和执行。该计划的会员有 15.9 美元 百万（直接费用）的癌症相关研究经费，其中 990 万美元用于同行评审，600 万美元用于 未经同行评审。同行评审资金包括近 640 万美元的 NIH 支持，其中 530 万美元是 来自国家癌症研究所。 NRTCB 计划成员拥有良好的计划互动记录，16 个国家就证明了这一点 外部资助的方案赠款。事实证明，成员继续取得杰出的研究进展 过去 5 年发表了超过 321 篇癌症相关出版物，其中 25% 和 70% 涉及癌症内部和外部 计划合作，52% 是机构间合作。主要科学成就包括新颖 发现 (1) 雄激素受体在乳腺癌对内分泌治疗耐药性中的作用，(2) 肝癌中的 NR、CAR，(3) 抑制 COUP-TFII 所需的新型 miRNA 调节信号轴 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控制细胞骨架动力学中的作用，(6) 用于 SRC-3 驱动致癌的表观遗传激活中 Warburg 相关糖酵解重编程 转录程序，以及（7）前列腺癌相关 SPOP 突变在调节中的作用 雄激素受体周转。转化进展包括：(1) NR4A 激活剂的临床前验证， 二氢麦角胺作为 AML 的新型治疗药物，(2) 四项新的研究者发起的试验，包括： 他莫昔芬用于治疗膀胱癌； meclizine，一种 CAR 反向激动剂，用于治疗肝癌； 舍曲林用于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- 的新型一流疗法的商业开发 3 与 Coactigon Inc.