Abstract A30: Preclinical study of a combination of mocetinostat (HDAC inhibitor) and 5-AZA-dC (decitabine) in chondrosarcoma

Abstract

Abstract Chondrosarcomas are the second most frequently occurring type of bone malignancy, and account for approximately 25% of all bone sarcomas. They are often highly aggressive neoplasms that rapidly progress and eventually recur and give distant metastases. They are largely considered to be resistant to conventional chemotherapy and radiotherapy. Previous reports have shown that the interaction of DNA methylation and histone modification regulates gene expression, and targeting these mechanisms could be a potentially novel approach to treat cancer. In the present study, we hypothesized that concurrent inhibition of histone acetylation and DNA methylation could result in decreased viability of chondrosarcoma cells. To test this, we used a panel of chondrosarcoma cell lines including IDH wild type (CH2879), IDH1 mutant (JJ012), and IDH2 mutant (SW1353) cell line. Results from our in vitro proliferation assay showed that combination of sub-IC50 concentrations of the DNA methyltransferase (DNMT) inhibitor decitabine (5-AZA-dC) and a spectrum-selective class I and IV histone deacetylase (HDAC) inhibitor mocetinostat (MGCD0103) resulted in decreased cell viability, which appears to be at least additive, in all the three chondrosarcoma cell lines when compared to either of the two drugs alone. Western blot analysis showed induction of cleaved Poly-ADP Ribose Polymerase (PARP) as well as cleaved caspase 3, known markers of apoptosis. Consistent with augmented DNA damage, combination of decitabine and MG103 markedly increased the levels of phospho-H2AX, a DNA damage marker, and proapoptotic BH3-only proteins such as Bim. Combination treatment also resulted in increased induction of histone acetylation (AcH3 and AcH4) and increased expression of E-cadherin, an important tumor suppressor gene. Cell cycle analysis showed induction of sub-G1 population phase in combination treatment. Previous reports have shown that CpG methylation is a critical event in transcriptional repression of hypermethylated genes in cancer. To this end, we show that combination treatment with mocetinostat and 5-AZA-dC results in downregulation of (H3K9) methylation. Taken together, our data strongly suggest that combination treatment with mocetinostat and decitabine is a novel treatment approach and merits evaluation in the treatment of chondrosarcoma. Citation Format: Tahir N. Sheikh, Parag Patwardhan, Gary K. Schwartz. Preclinical study of a combination of mocetinostat (HDAC inhibitor) and 5-AZA-dC (decitabine) in chondrosarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A30.