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Targeting Histone Deacetylases with Small Moleule Inhibitors in Ovarian Cancer

用小分子抑制剂靶向卵巢癌中的组蛋白脱乙酰酶

基本信息

批准号：
7871853
负责人：
Dineo Khabele
金额：
$ 15.91万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7871853
关键词：
Address Apoptosis Area Binding Biochemical Biological Assay Biology Cancer cell line Cell Death Cell Proliferation Cell Survival Cell physiology Cells Chromatin Cisplatin Clinical Clinical Trials Collaborations DNA DNA Adducts DNA Damage DNA Repair Data Development Plans Disease Dose-Limiting Drug resistance Exhibits Family Foundations Funding Gene Silencing Genetic Transcription Goals Gynecologic HDAC3 gene Histone Deacetylase Histone Deacetylase Inhibitor Histone deacetylase inhibition Histones In Vitro Individual Institutes Institution Investigation Ketones Knowledge Liposomes Malignant Neoplasms Malignant neoplasm of ovary Mentors Mentorship Methods Normal Cell Pharmaceutical Preparations Physical condensation Physicians Platinum Pre-Clinical Model Preparation Property Proteins Publishing Records Regimen Relative (related person)Repressor Proteins Research Research Design Resistance Resources Scientist Small Interfering RNA System Testing Therapeutic Toxic effect Training Universities Work anticancer research antitumor agent base cancer cell career career development chemotherapy design experience high throughput screening in vivo inhibitor/antagonist insight mouse model neoplastic cell novel novel strategies pre-clinical preclinical study public health relevance response skills skills training small molecule standard care tool treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer remains the deadliest gynecologic malignancy. Despite advances in standard platinum-based treatment, new approaches are needed to make a positive impact on this disease. Histone deacetylase inhibitors (HDACi) have potent anti-tumor effects in ovarian cancer cells that are resistant to the DNA- damaging agent cisplatin, a first-line treatment for ovarian cancer. The candidate has recently published that HDAC inhibition with class I selective HDACi and small interfering RNA (siRNA) gene silencing of class I HDACs, particularly HDAC3 suppress cell proliferation in ovarian cancer cells. Dr. Scott Hiebert, the candidate's primary mentor has recent work showing that conditional knockdown of HDAC3 triggers apoptosis and DNA damage. Through a special collaboration with her secondary mentor Dr. Stuart Schreiber at the Broad Institute of MIT and Harvard, the candidate performed a high-throughput screen of class I HDACi in ovarian cancer cells. She found BRD7914, a unique small molecule, decreased cell viability and induced apoptosis and histone marks of DNA damage. Moreover even in cisplatin-resistant cells, BRD7914 was synergistic with cisplatin. BRD7914 exhibits potent HDAC3 inhibitory binding and is derived from a brand new class of electrophilic ketones. These results are in line with emerging evidence that HDAC3 inhibition is a key contributor to chromatin decondensation resulting in an impaired response to DNA damage and led to the underlying hypothesis: a rational treatment strategy for ovarian cancer is the combination of HDAC3-biased HDACi and platinum-based chemotherapy. Preclinical models of ovarian cancer will be used to test the specific hypotheses that: 1) DNA damage is a component of apoptosis induced by BRD7914, a novel HDACi with potent HDAC3 inhibitory binding; 2) HDAC3 inhibition enhances DNA damage-induced apoptosis; and 3) HDAC3-biased HDACi are synergistic with cisplatin, a DNA damaging agent. Significance: This proposal will better define the anti-tumor properties of BRD7914, a new small molecule inhibitor biased towards HDAC3, advance current knowledge of HDAC3 as a potential target for therapy and provide important preclinical insights into the clinical merits of combining BRD7914 and other HDAC3-biased HDACi with platinum-based chemotherapy in the treatment of ovarian cancer. Dr. Scott Hiebert will mentor the candidate's scientific and career development at Vanderbilt University. Dr. Stuart Schreiber at the Broad Institute of MIT and Harvard will serve as a secondary mentor. Both mentors and resource-rich institutions have outstanding track records of training physician-scientists. Accomplishing the aims along with the individualized research and career development plans will significantly maximize the candidate's chance of establishing a long-term scientific career in translational cancer research. PUBLIC HEALTH RELEVANCE: The goals of this research are to 1) better define the anti-tumor properties of BRD7914, a unique small molecule biased towards HDAC3 inhibition, 2) advance current knowledge of HDAC3 as a potential target for therapy and 3) provide important preclinical insights into the clinical merits of combining BRD7914 and other HDAC3-biased HDACi with platinum-based chemotherapy in the treatment of ovarian cancer. The use of novel compounds and novel approaches of probing the biology of HDAC3 and other HDACs in ovarian cancer with small molecule inhibitors will allow the candidate to gain new research skills and training in several areas under the mentorship of Dr. Scott Hiebert (Vanderbilt University) and Dr. Stuart Schreiber (The Broad Institute of MIT and Harvard) in preparation for an independent career in translational cancer research.

描述（由申请人提供）：卵巢癌仍然是最致命的妇科恶性肿瘤。尽管标准铂类药物治疗取得了进展，但仍需要新的方法来对这种疾病产生积极影响。组蛋白去乙酰化酶抑制剂（HDACi）在对DNA损伤剂顺铂（卵巢癌的一线治疗药物）耐药的卵巢癌细胞中具有有效的抗肿瘤作用。该候选人最近发表了用I类选择性HDACi和I类HDAC的小干扰RNA（siRNA）基因沉默抑制HDAC，特别是HDAC 3抑制卵巢癌细胞中的细胞增殖。候选人的主要导师Scott Hiebert博士最近的研究表明，HDAC 3的条件性敲低会引发细胞凋亡和DNA损伤。通过与她在麻省理工学院和哈佛布罗德研究所的二级导师Stuart Schreiber博士的特别合作，这位候选人在卵巢癌细胞中进行了I类HDACi的高通量筛选。她发现BRD 7914是一种独特的小分子，它降低了细胞活力，诱导了细胞凋亡和DNA损伤的组蛋白标记。此外，即使在顺铂耐药细胞中，BRD 7914与顺铂也具有协同作用。BRD 7914具有强效HDAC 3抑制性结合，并衍生自一类全新的亲电子酮。这些结果与新出现的证据一致，即HDAC 3抑制是导致对DNA损伤的反应受损的染色质去凝聚的关键因素，并导致潜在的假设：卵巢癌的合理治疗策略是HDAC 3偏向的HDACi和基于铂的化疗的组合。卵巢癌的临床前模型将用于测试以下特定假设：1）DNA损伤是BRD 7914诱导的细胞凋亡的组成部分，BRD 7914是一种具有有效HDAC 3抑制性结合的新型HDACi; 2）HDAC 3抑制增强DNA损伤诱导的细胞凋亡;以及3）HDAC 3偏向的HDACi与顺铂（一种DNA损伤剂）协同作用。重要性：该提案将更好地定义BRD 7914的抗肿瘤特性，BRD 7914是一种偏向HDAC 3的新型小分子抑制剂，推进了HDAC 3作为治疗潜在靶点的现有知识，并为BRD 7914和其他HDAC 3偏向HDACi与铂类化疗联合治疗卵巢癌的临床优点提供了重要的临床前见解。Scott Hiebert博士将指导候选人在范德比尔特大学的科学和职业发展。麻省理工学院和哈佛布罗德研究所的斯图尔特·施赖伯博士将担任二级导师。导师和资源丰富的机构在培训医生-科学家方面都有出色的记录。实现目标沿着个性化的研究和职业发展计划将显着最大限度地提高候选人的机会，建立一个长期的科学职业生涯在转化癌症研究。公共卫生关系：本研究的目的是：1）更好地定义BRD 7914（一种偏向HDAC 3抑制的独特小分子）的抗肿瘤特性，2）推进HDAC 3作为潜在治疗靶点的现有知识，3）为BRD 7914和其他HDAC 3偏向HDACi与铂基化疗联合治疗卵巢癌的临床优点提供重要的临床前见解。使用新化合物和新方法探测HDAC 3和其他HDAC在卵巢癌中的生物学与小分子抑制剂将使候选人获得新的研究技能和培训在几个领域的指导下斯科特·希伯特博士（范德比尔特大学）和斯图尔特·施赖伯博士（麻省理工学院和哈佛的布罗德研究所），为转化癌症研究的独立职业生涯做准备。