Abstract 5381: Therapeutic potential of HDAC inhibitors in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)

Abstract

Abstract SCCOHT is a rare but deadly type of ovarian cancer. It mainly affects young women with the median age about 28 years. Although often diagnosed at an early stage, the prognosis of SCCOHT is nonetheless dismal with a 2-year survival less than 35% due to lack of effective treatments. Unlike common malignancies, the genome of SCCOHT is minimally disturbed. Recently, we and others have discovered inactivating mutations of SMARCA4, the ATPase of the SWI/SNF chromatin remodeling complex, in the majority of SCCOHT along with loss of SMARCA4 protein. Interestingly, SMARCA2, the alternative ATPase of the SWI/SNF complex is also inactivated in SCCOHT without apparent mutations. Re-expression of either SMARCA4 or SMARCA2 robustly inhibited the growth of SCCOHT cells. Therefore, the dual deficiency of SMARCA4 and SMARCA2 may be the primary driver in SCCOHT tumorigenesis by creating distinct epigenetic features that promote oncogenic transformation and can serve as promising therapeutic targets. In an attempt to identify epigenetic drugable targets, we performed the drug screening using an epigenetic drug library (Cayman Chemical) in two SCCOHT cell lines and four other ovarian cancer cell lines with intact SMARCA4 and SMARCA2. We identified several HDAC inhibitors that selectively inhibited the viability of SCCOHT cells (BIN67 and SCCOHT1) compared to that of other ovarian cancer cell lines. We confirmed that in comparison to other ovarian cancer cell lines, SCCOHT cells were significantly more sensitive to the treatment of several pan-HDAC inhibitors including SAHA, an FDA-approved HDAC inhibitor for treatment of cutaneous T cell lymphoma, and two selective HDAC6 inhibitors (CAY10603 and Nexturastat A), but not to Romidepsin, a selective HDAC1/2 inhibitor. Furthermore, the expression of HDAC6 was significantly higher in SCCOHT cells compared with other ovarian cancer cell lines and re-expression of SMARCA4 suppressed the expression of HDAC6. Interestingly, SCCOHT cells were also more sensitive to Pracinostat, a broad HDAC inhibitor with minimum effect on HDAC6. Using Agilent gene expression array, we identified a subset of genes whose expression was upregulated by both SMARCA4 re-expression and SAHA treatment in BIN67 cells. Taken together, our data suggest that the SMARCA4/SMARCA2 dual deficiency may promote hypersensitivity to HDAC inhibitors through both HDAC6-dependent and independent pathways. Ongoing studies will address the detailed mechanisms and evaluate the efficacy of using HDAC inhibitors for the treatment of SCCOHT cell line-derived and patient-derived mouse xenografts to provide requisite evidence for initiating a clinical trial for defeating this notorious disease. Citation Format: Yemin Wang, Pilar Ramos, Anthony N. Karnezis, Jeffrey M. Trent, David G. Huntsman. Therapeutic potential of HDAC inhibitors in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5381. doi:10.1158/1538-7445.AM2015-5381