The selective proteasome inhibitor carfilzomib synergizes with the histone deacetylase (HDAC) inhibitor vorinostat in preclinical models of non-Hodgkin’s lymphoma and solid tumors

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA A43 Carfilzomib is a first in class tetrapeptide epoxyketone proteasome inhibitor with selectivity for the chymotrypsin-like active site. Carfilzomib has demonstrated promising safety and anti-tumor activity in Phase I and is currently in Phase II clinical studies in multiple myeloma and solid tumors (Alsin. M. et. al., Blood (ASH Annual Meeting Abstracts), Nov 2007; 110: Abstract 411.) . Combinations of the histone deacetylase (HDAC) inhibitor vorinostat, which is approved for the treatment of cutaneous T cell lymphoma (CTCL), and proteasome inhibitors results in a synergistic increase in apoptosis in hematologic tumor cell lines. This enhanced activity corresponds to alterations in cell cycle regulation, increased oxidative stress and induction of the unfolded protein response (Marks. P. et. al.,Oncogene. 2007 Feb 26;26(9):1351-6 7). To establish the potential synergy of vorinostat and carfilzomib we initially assessed these agents in immunocompromised (BNX) mice bearing tumor xenografts of the RL (non-Hodgkin’s lymphoma) cell line. Single agent carfilzomib mediated an anti-tumor response in this model but only at its MTD (5 mg/kg). BNX mice with established tumors were treated with carfilzomib, administered on the dose schedule currently being employed in phase II trials (QDx2 repeated weekly), vorinostat, administered daily for 5 consecutive days and repeated weekly, or a combination of the two agents. We chose a sub-MTD dose of carfilzomib (3 mg/kg) in order to assess enhanced anti-tumor activity in vivo. The combination therapy induced a 48% reduction in tumor growth, as compared to vehicle treated animals, while neither single agent induced a significant anti-tumor response. Toxicity, as measured by weight loss, was similar amongst the treatment groups suggesting that the combination was well tolerated in experimental animals. We extended these findings of synergistic anti-tumor activity in our hematologic tumor model to in vitro studies with ovarian (ES-2) and renal (786-O) tumor cell lines. Synergistic cytotoxic effects, as indicated by combination index (CI) values of 0.35 and 0.76, were noted in the ES-2 and 786-O cell lines, respectively. Taken together, these data suggest that the combination vorinostat and carfilzomib is active across multiple tumor histotypes and is well tolerated and efficacious in mouse models of human tumors. Our findings support further preclinical investigation and clinical testing of this therapeutic regimen in both hematologic and solid tumor malignancies.