Inhibition Of HDAC6 In Combination With Targeted Agents Results In Broad Synergistic Decreases In Viability In Non-Hodgkin’s Lymphoma (NHL) Cells

Histone Deacetylase (HDAC) inhibitors have demonstrated significant clinical benefit as single agents in cutaneous and peripheral T cell lymphomas, and have received FDA approval for these indications. Numerous clinical studies are also ongoing to investigate the potential benefit of combining HDAC inhibitors with other standard of care and investigational agents in various subtypes of lymphoma. ACY-1215 is a first-in-class, orally available selective inhibitor of HDAC6 (approximately 11-fold selective over class I HDAC’s) that is currently in two Phase Ib clinical trials (NCT01323751 and NCT01583283) in combination with dexamethasone and either bortezomib or lenalidomide in multiple myeloma (MM) patients. Beyond MM, preclinical studies in NHL cell lines also demonstrated increased benefit from treatment with ACY-1215 in combination with the proteasome inhibitors bortezomib or carfilzomib (Amengual, et al, ASH, 2012; Dasmahapatra, et al, ASH, 2012). In addition to standard of care therapies, a number of novel targeted agents have recently demonstrated potential clinical benefit in subtypes of NHL, including agents targeting Bruton’s tyrosine kinase (eg. ibrutinib) and the phosphatidyl inositol-3’ kinase family (eg. GS-1101, IPI-145, and GDC-0941). We describe here the therapeutic potential of ACY-1215 in a collection of NHL cell lines both as a single agent and in combination with these novel targeted agents.

NHL cell lines derived from diffuse large B cell lymphomas (DLBCL; both germinal center and activated B cell type) and mantle cell lymphomas (MCL) exhibit significantly decreased viability in response to treatment with selective inhibitors of HDAC6, including both ACY-1215 and ACY-775 (approximately 300-fold selective for HDAC6 over HDAC1/2, and 1500-fold selective over HDAC3). Furthermore, combination treatment of NHL lines with ACY-1215 and either ibrutinib, GDC-0941, or GS-1101, in a dose-matrix format resulted in synergistic decreases in cell viability. The relevance of HDAC6 inhibition to this synergistic response was confirmed through the observation of similarly decreased viability when treating cells in combination with the highly selective HDAC6 inhibitor ACY-775. Detailed molecular mechanism of action studies are ongoing and will be presented. Additional studies are also underway to assess the tolerability and efficacy of combinations of these targeted agents with ACY-1215 in xenograft models of lymphoma. Overall, these data support the continued investigation of the activity of ACY-1215 in lymphoma both as a single agent and in combination with the next generation of targeted therapies for B cell lymphomas.