Nuclear Receptor, Transcription and Chromatin Biology Program

核受体、转录和染色质生物学项目

• 批准号: 10439821
• 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/10439821
• 关键词: 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; 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; 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 Intervention; Training; Transcriptional Regulation; Translational Research; Translations; United States National Institutes of Health; Validation; Walkers; apoAI regulatory protein-1; cancer cell; cancer clinical trial; carcinogenesis; chromatin remodeling; 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）程序 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 与NR依赖性和表观遗传机制相关的发现转录调节的转换的翻译 致癌作用，以加速新的预防和治疗干预措施的发展。这 程序有2个主要主题：（1）鉴定有助于癌症发病机理和进展的NRS， 披露其作用机制，并评估其作为新的治疗靶标的潜力，以及（2） 介导癌症转录表观遗传调节的染色质调节剂的生物学和功能。这 计划有20名积极资助的研究成员，2名临床，2个辅助人员，一名共享成员与 与两个主题相关的广泛研究经验，并从包括医学在内的多个部门获取， 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是雌激素受体作用的转化研究专家，以及2个共同 领导者，国际公认的环境，遗传和表观遗传因素专家谢丽尔·沃克（Cheryl Walker）博士 癌症的相互作用和具有丰富肿瘤学经验的临床研究人员Nicholas Mitsiades博士 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 与癌症相关的研究资金中的百万（直接费用），其中990万美元经过同行评审，600万美元是 非同行评审。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 来自NCI。 NRTCB计划成员的编程互动记录很强，如16所证明 外部资助的程序赠款。成员继续取得杰出的研究进展 在过去的5年中，超过321个与癌症相关的出版物，其中25％和70％涉及内部和间 程序合作和52％的机构间。主要的科学成就包括小说 （1）雄激素受体在乳腺癌对内分泌疗法耐药性中的作用，（2） NR，肝癌中的CAR，（3）抑制政府TFII所需的新型miRNA调节信号轴 驱动的前列腺癌转移，（4）糖皮质激素受体作为Runx1-Eto的新型治疗靶标 阳性急性髓样白血病，（5）表观遗传调节剂在控制细胞骨架动力学中的作用，（6）作用 用于与沃堡相关的糖酵解重编程，用于SRC-3驱动致癌的表观遗传激活 转录程序，以及（7）前列腺癌与SPOP相关突变的作用在调节中 雄激素受体转换。翻译进展包括：（1）NR4A激活剂的临床前验证， 二氢甲胺作为AML的新型治疗药物，（2）四个新研究者发起的试验，包括： 他莫昔芬治疗膀胱癌； Meclizine，一种用于治疗肝癌的汽车反向激动剂； 舍曲林治疗骨髓增生综合征；男性激素治疗反应中的种族差异 使用转移性前列腺癌，以及（3）针对SRC-的新的第一类疗法的商业开发 3与Coactigon Inc.