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

• 批准号: 8460917
• 负责人: Dineo Khabele
• 金额: $ 15.91万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/8460917
• 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; research and development; response; skills; skills training; small molecule; standard care; tool; treatment strategy; tumor; tumor growth

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.

描述(申请人提供)：卵巢癌仍然是最致命的妇科恶性肿瘤。尽管在基于铂的标准治疗方面取得了进展，但需要新的方法才能对这种疾病产生积极影响。组蛋白去乙酰酶抑制剂(HDACi)在卵巢癌细胞中具有强大的抗肿瘤作用，这些细胞对DNA损伤剂顺铂具有耐药性，顺铂是治疗卵巢癌的一线药物。这位候选人最近发表了通过抑制I类选择性HDACi和小干扰RNA(SiRNA)基因沉默I类HDAC，特别是HDAC3抑制卵巢癌细胞的增殖。这位候选人的主要导师斯科特·希伯特博士最近的研究表明，有条件地敲除HDAC3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大学的二级导师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的高通量筛查。她发现，BRD7914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损伤的组蛋白标志。此外，即使在顺铂耐药的细胞中，BRD7914也与顺铂有协同作用。BRD7914显示出强大的HDAC3抑制结合，并从一种全新的亲电酮衍生而来。这些结果与新出现的证据一致，即HDAC3抑制是染色质解缩的关键因素，导致对DNA损伤的反应减弱，并导致潜在的假设：卵巢癌的合理治疗策略是偏向HDAC3的HDACi和以铂为基础的化疗的组合。卵巢癌的临床前模型将被用来检验以下具体假设：1)DNA损伤是BRD7914诱导的细胞凋亡的一个组成部分，BRD7914是一种新型的HDACi，具有强大的HDAC3抑制结合；2)HDAC3抑制增强了DNA损伤诱导的细胞凋亡；以及3)基于HDAC3的HDACi与DNA损伤剂顺铂有协同作用。意义：这项建议将更好地确定BRD7914的抗肿瘤特性，这是一种偏向HDAC3的新型小分子抑制剂，促进了对HDAC3作为潜在治疗靶点的现有知识，并为将BRD7914和其他偏向HDAC3的HDACi与以铂为基础的化疗相结合治疗卵巢癌的临床优点提供了重要的临床前见解。斯科特·希伯特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大学博德学院的斯图尔特·施赖伯博士将担任第二导师。导师和资源丰富的机构在培训内科科学家方面都有出色的记录。实现这些目标以及个性化的研究和职业发展计划将使候选人在转化型癌症研究中建立长期科学生涯的机会大大增加。