Abstract A187: Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models

Abstract

Abstract Combinations of HDAC inhibitors with chemotherapeutic agents have demonstrated evidence of clinical benefit, for example in ovarian cancer combining belinostat with carboplatin and paclitaxel (Dizon, Int J Gynecol Cancer, 2012), and disease stabilization with vorinostat and tamoxifen in hormone receptor therapy-refractory breast cancer patients (Munster, Br J Cancer, 2011). However, the toxicity profile of pan-HDAC inhibitors frequently limits their use in combination with other drugs commonly used in hematologic and solid tumors. The search for combination therapies that are better tolerated has motivated the development of more selective HDAC inhibitors with improved safety profiles. ACY-241 is a new, orally available and selective histone deacetylase (HDAC) 6 inhibitor under clinical development in combination with pomalidomide and dexamethasone in multiple myeloma (NCT02400242). ACY-241 has the potential for a substantially reduced side effect profile versus current nonselective HDAC inhibitor drug candidates due to reduced potency against Class I HDACs while retaining the potential for anticancer effectiveness. In this study the potential activity of ACY-241 in combination with paclitaxel was explored in preclinical models of solid tumors. In cell lines generated from multiple solid tumor lineages, combination treatment with ACY-241 and paclitaxel resulted in enhanced inhibition of proliferation and increased cell death relative to either single agent alone. The combination of ACY-241 plus paclitaxel also demonstrated enhanced efficacy in xenograft models of pancreatic and ovarian cancer relative to either single agent. Combination dosing was well tolerated as treated animals continued to gain weight throughout the dosing period, and similar results were obtained when ricolinostat, an alternative HDAC6 inhibitor, was tested in combination with paclitaxel. Beyond cell cycle arrest and apoptosis, treatment with paclitaxel was recently shown to induce multipolar spindle formation during mitosis, subsequently leading to aberrant cell division and death (Zasadil, Sci Transl Med, 2014). While ACY-241 treatment alone had minimal effect on mitotic spindle formation, combination treatment with ACY-241 and paclitaxel resulted in more frequent occurrence of mitotic cells with multipolar spindles. Thus, in addition to potentially blocking entry into S phase, combination treatment also leads to increased frequency of aberrant mitoses. At the molecular level, treatment with paclitaxel results in enhanced stability of microtubules, which in turn leads to increased acetylation of α-tubulin. HDAC6 directly regulates acetylation of α-tubulin, and ACY-241 treatment results in a dose-dependent increase in α-tubulin hyperacetylation. The enhanced anti-cancer efficacy resulting from combination treatment with ACY-241 and paclitaxel in cell lines was associated with further increased hyperacetylation of α-tubulin, suggesting these agents synergistically impact the regulation of tubulin biology. The enhanced efficacy of ACY-241 plus paclitaxel 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, Morgan Jordan, Min Yang, Simon S. Jones, Steven N. Quayle. Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A187.