Abstract 5456: ACY-1215, a selective inhibitor of HDAC6, synergizes with immunomodulatory drugs (IMiDs) to induce apoptosis of multiple myeloma (MM) cells
Authors: Quayle Steven N. , Tamang David , Yang Min , Jones Simon S. 
Published: May 2015

Abstract
Histone deacetylase (HDAC) enzymes represent attractive therapeutic targets in MM, but non-selective HDAC inhibitors have led to dose-limiting toxicities in patients, particularly in combination with other therapeutic agents. ACY-1215 is a first-in-class, orally available HDAC inhibitor that is 11-fold selective for HDAC6, and synergizes in vitro and in vivo with bortezomib in preclinical models of MM without inducing unfavorable toxicities (Blood, 20[210]: 4061). In support of its potential tolerability benefits, ongoing Phase Ib clinical trials with ACY-1215 have thus far demonstrated an excellent safety and tolerability profile (Yee, et al, ASH, 2013). The IMiD class of drugs, including lenalidomide and pomalidomide, exhibit striking anti-myeloma properties in a variety of MM models, and have demonstrated significant clinical activity in MM patients. Prior clinical studies have demonstrated activity of the non-selective HDAC inhibitor vorinostat in combination with lenalidomide and dexamethasone in MM patients (Richter, et al, ASH, 2011). However, many patients experienced considerable toxicities with this regimen that significantly limited clinical utility. In support of our ongoing clinical development program for ACY-1215 in MM, we show here that combining ACY-1215 with either IMiD leads to synergistic decreases in the viability of MM cells in vitro. The relevance of inhibition of HDAC6 to this effect was validated by demonstrating synergistic interactions of either IMiD molecule with ACY-775, which is more than 300-fold selective for HDAC6 over class I HDAC's. Time course studies demonstrated accumulation of cell cycle arrest in cells after prolonged exposure to either IMiD, as well as progressive induction of apoptosis in these cells. Notably, though, the addition of ACY-1215 to either IMiD resulted in synergistic increases in the percentage of MM cells undergoing apoptosis. At the molecular level, MM cells are known to be dependent on expression of the MYC and IRF4 transcription factors. Both ACY-1215 and IMiDs as single agents reduced expression of the critical genes MYC and IRF4, which were reduced even further by combination treatment. The molecular mechanism underlying this effect is currently being explored. Finally, the combination of ACY-1215, lenalidomide, and dexamethasone was well tolerated in vivo with no overt evidence of toxicity, and combination efficacy studies with this combination are now being explored in models of MM. By demonstrating that a selective inhibitor of HDAC6 synergizes with IMiD's while maintaining an improved safety profile, these results provided a rational basis for the clinical development of the orally available combination of ACY-1215 and lenalidomide plus dexamethasone in the ongoing Phase Ib clinical trial (NCT01583283) for the treatment of MM.
Citation Format: Steven N. Quayle, David Tamang, Min Yang, Simon S. Jones. ACY-1215, a selective inhibitor of HDAC6, synergizes with immunomodulatory drugs (IMiDs) to induce apoptosis of multiple myeloma (MM) cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5456. doi:10.1158/1538-7445.AM2014-5456