Abstract 4822: Combination efficacy of the selective HDAC inhibitor ACY-241 and paclitaxel in solid tumor models

Abstract

Abstract ACY 241 is a new, orally available and selective histone deacetylase (HDAC) 6 inhibitor in clinical development in combination with pomalidomide and dexamethasone in multiple myeloma. Like the structurally related drug ricolinostat (ACY-1215), ACY-241 has the potential for a substantially reduced side effect profile versus current nonselective HDAC inhibitor candidates due to reduced potency against Class I HDACs while retaining the potential for anticancer effectiveness. One of the major effects of HDAC6 inhibition is hyperacetylation of á-tubulin, which is suggestive of potential combination activity with taxanes in cancer treatment. Paclitaxel is a chemotherapeutic agent approved for use in the treatment of multiple solid tumor types, including breast cancer, ovarian cancer, non-small cell lung cancer and Kaposi's sarcoma (Weaver, 2014). Recent studies indicate that clinically relevant low concentrations of paclitaxel caused multipolar spindle formation resulting in aberrant mitosis and cell death, which further contributes to the anti-cancer efficacy of paclitaxel (Zasadil et al., 2014). In cell lines, combination treatment with ACY-241 and paclitaxel resulted in enhanced inhibition of proliferation and increased cell death. The combination of ACY-241 plus paclitaxel also demonstrated enhanced efficacy in xenograft models of pancreatic and ovarian cancer. Cell-cycle analysis indicated that ACY-241 treatment in combination with paclitaxel caused synergistic inhibition of tumor cell proliferation through enhanced reduction of DNA replication in S-phase and increased induction of cell death and aneuploidy. ACY-241 treatment in combination with paclitaxel did not increase mitotic arrest but did increase the frequency of multipolar spindle formation during mitosis, leading to aberrant mitoses, abnormal nuclei, and cell death in agreement with a previous report (Zasadil et al). At the molecular level, the enhanced anti-cancer efficacy resulting from combination treatment with ACY-241 and paclitaxel in cell lines was associated with further increased hyperacetylation of á-tubulin, suggesting these agents synergistically impact the regulation of tubulin biology. Interestingly,gamma-tubulin was not always detectable at each pole of these multipolar spindles, suggesting that multipolar spindle formation may be independent of centrosome amplification and/or splitting. Additional studies investigating the association between localization of spindle proteins and multipolar spindle formation are in progress. The enhanced efficacy of paclitaxel plus ACY-241 observed here, in addition to the anticipated superior safety profile of a selective HDAC6 inhibitor, provides a strong rationale for clinical development of this combination in patients with advanced solid tumors. Citation Format: Pengyu Huang, Ingrid Almeciga-Pinto, Min Yang, Simon S. Jones, Steven N. Quayle. Combination efficacy of the selective HDAC inhibitor ACY-241 and paclitaxel in solid tumor models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4822.