Abstract 5380: Selective HDAC inhibition by ricolinostat (ACY-1215) or ACY-241 synergizes with IMiD® immunomodulatory drugs in Multiple Myeloma (MM) and Mantle Cell Lymphoma (MCL) cells (2015)

Abstract Histone deacetylase (HDAC) enzymes are attractive therapeutic targets in oncology, but non-selective HDAC inhibitors have led to dose-limiting toxicities in patients, particularly in combination with other therapeutic agents. Ricolinostat (ACY-1215), a first-in-class orally available HDAC inhibitor that is 11-fold selective for HDAC6, synergizes in vitro and in vivo with bortezomib in models of MM (Santo, Blood, 2012) and with carfilzomib in models of lymphoma (Dasmahapatra, Mol Cancer Ther, 2014). Furthermore, ricolinostat has demonstrated an excellent safety and tolerability profile in Phase I trials (Raje, Haematologica, 2014, Suppl 1). In addition to ongoing clinical studies with ricolinostat, we have identified ACY-241 as a next generation, orally available, selective inhibitor of HDAC6 for clinical evaluation. The IMiD® immunomodulatory class of drugs, including lenalidomide (len) and pomalidomide (pom), exhibit striking anti-myeloma properties in a variety of MM models, and have demonstrated significant clinical activity in MM patients. Beyond MM, len is also approved for the treatment of MCL patients. In support of our ongoing clinical development programs for ricolinostat and ACY-241, we show here that combinations with either len or pom leads to synergistic decreases in the viability of MM and MCL cells in vitro. Time course studies demonstrated accumulation of cell cycle arrest in cells after prolonged exposure to len or pom, as well as progressive induction of apoptosis in these cells. Notably, though, the addition of ricolinostat or ACY-241 to either len or pom resulted in synergistic increases in the percentage of MM and MCL cells undergoing apoptosis. At the molecular level, treatment with IMiD® immunomodulatory compounds reduced expression of the critical transcription factors MYC and IRF4, which were reduced even further by treatment with ricolinostat or ACY-241 in combination with either len or pom. The molecular mechanism underlying this effect is currently being explored, though retention of low level inhibition of HDAC1, 2, and 3 by these compounds may contribute to the enhanced effects on gene expression reported here in combination with len or pom. Finally, prolonged treatment with ACY-241 plus pomalidomide was well tolerated in vivo with no overt evidence of toxicity, and combination treatment resulted in a significant extension of survival in a xenograft model of MM. Given the comparable tolerability profiles of ricolinostat and ACY-241, and their preclinical activity in combination with IMiD® immunomodulatory drugs, these findings support clinical evaluation of these agents in MM and MCL patients. Citation Format: Steven N. Quayle, Ingrid Almeciga-Pinto, David Tamang, Min Yang, Simon S. Jones. Selective HDAC inhibition by ricolinostat (ACY-1215) or ACY-241 synergizes with IMiD® immunomodulatory drugs in Multiple Myeloma (MM) and Mantle Cell Lymphoma (MCL) cells. [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 5380. doi:10.1158/1538-7445.AM2015-5380