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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA148887-03
Application #
8260292
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ojeifo, John O
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$159,084
Indirect Cost
$11,784
Name
Vanderbilt University Medical Center
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Wilson, Andrew J; Stubbs, Matthew; Liu, Phillip et al. (2018) The BET inhibitor INCB054329 reduces homologous recombination efficiency and augments PARP inhibitor activity in ovarian cancer. Gynecol Oncol 149:575-584
Wilson, Andrew J; Sarfo-Kantanka, Kofi; Barrack, Toby et al. (2016) Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib. Gynecol Oncol 143:143-151
Wilson, Andrew J; Fadare, Oluwole; Beeghly-Fadiel, Alicia et al. (2015) Aberrant over-expression of COX-1 intersects multiple pro-tumorigenic pathways in high-grade serous ovarian cancer. Oncotarget 6:21353-68
Carrillo, Alexia M; Hicks, Mellissa; Khabele, Dineo et al. (2015) Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells. Mol Cancer Res 13:1197-205
Wilson, Andrew J; Saskowski, Jeanette; Barham, Whitney et al. (2015) Microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer. Mol Cancer 14:192
Stewart, Michelle L; Tamayo, Pablo; Wilson, Andrew J et al. (2015) KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine. Cancer Res 75:2897-906
Wilson, Andrew J; Saskowski, Jeanette; Barham, Whitney et al. (2015) Thymoquinone enhances cisplatin-response through direct tumor effects in a syngeneic mouse model of ovarian cancer. J Ovarian Res 8:46
Khabele, Dineo (2014) The therapeutic potential of class I selective histone deacetylase inhibitors in ovarian cancer. Front Oncol 4:111
Hull, Pamela C; Williams, Elizabeth A; Khabele, Dineo et al. (2014) HPV vaccine use among African American girls: qualitative formative research using a participatory social marketing approach. Gynecol Oncol 132 Suppl 1:S13-20
Khabele, Dineo; Kabir, Syeda M; Dong, Yuanlin et al. (2014) Preferential effect of akt2-dependent signaling on the cellular viability of ovarian cancer cells in response to EGF. J Cancer 5:670-8

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