Targeting Histone Deacetylases with Small Moleule Inhibitors in Ovarian Cancer

描述（由申请人提供）：卵巢癌仍然是最致命的妇科恶性肿瘤。尽管标准的铂基治疗取得了进展，但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）对抗DNA损伤剂顺铂（卵巢癌的一线治疗药物）的卵巢癌细胞具有有效的抗肿瘤作用。该候选人最近发表了I类选择性HDAC抑制和I类HDAC，特别是HDAC3的小干扰RNA （siRNA）基因沉默抑制卵巢癌细胞的细胞增殖。候选人的主要导师Scott Hiebert博士最近的研究表明，有条件地敲低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布罗德研究所的第二导师Stuart Schreiber博士的特别合作，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BRD7914，一种独特的小分子，降低细胞活力，诱导细胞凋亡和DNA损伤的组蛋白标记。此外，即使在顺铂耐药细胞中，BRD7914也与顺铂具有协同作用。BRD7914表现出有效的抑制HDAC3结合，来源于一类全新的亲电酮。这些结果与新出现的证据一致，即HDAC3抑制是染色质去致密化的关键因素，导致对DNA损伤的反应受损，并导致了潜在的假设：卵巢癌的合理治疗策略是将HDAC3偏向的HDACi和铂基化疗相结合。卵巢癌临床前模型将用于验证以下特定假设：1)DNA损伤是一种具有强抑制HDAC3结合的新型HDACi BRD7914诱导细胞凋亡的一个组成部分；2)抑制HDAC3可促进DNA损伤诱导的细胞凋亡；3) hdac3偏倚HDACi与顺铂（一种DNA损伤剂）具有协同作用。意义：本提案将更好地定义新型HDAC3偏倚小分子抑制剂BRD7914的抗肿瘤特性，推进现有关于HDAC3作为潜在治疗靶点的认识，并为BRD7914与其他HDAC3偏倚的HDACi联合铂基化疗治疗卵巢癌的临床优势提供重要的临床前见解。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研究所的斯图尔特·施赖伯博士将担任副导师。导师和资源丰富的机构都在培养医生科学家方面有着出色的记录。完成这些目标以及个性化的研究和职业发展计划将极大地提高候选人在转化性癌症研究中建立长期科学职业生涯的机会。

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.