Targeting Histone Deacetylases with Small Moleule Inhibitors in Ovarian Cancer

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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.