Abstract 1709: Reovirus synergy with proteosome inhibitor carfilzomib and Akt inhibitor perifisone overcomes therapy resistance of multiple myeloma: promising preclinical activity

Abstract

Abstract Introduction: Multiple myeloma (MM) is a hematological malignancy of plasma cells and despite recent therapeutic advances that have increased the median survival rates of patients, is still currently felt to be incurable. We recently demonstrated the potential of reovirus as a novel therapeutic agent for several MM cell lines and ex vivo patient tumors. Therapy resistant disease however, still remains a problem. In the present study we demonstrate that reovirus acts synergistically with carfilzomib and/or perifisone in oncolysis of therapy resistant MM cell lines. Methods: The MM cell lines RPMI 8226, U266, NCIH929, U266, INA-6, KMS11 and OPM2 were incubated with live (LV) or UV-inactivated (DV) reovirus at a multiplicity of infection (MOI) of 40 for 24, 48, and 72 hours respectively and cell death was assessed via the WST assay. Reovirus resistant OPM2 and moderately sensitive KMS-11 as well as reovirus sensitive RPMI8226 were selected for combination therapy and treated with reovirus and drugs at various concentrations to evaluate Effective Dose 50% (ED50) values. ED50 values for each drug and reovirus was combined in various concentrations but with consistent ratios and percent of toxicity was determined. Using Calcusyn software, combination index (CI) values were generated and synergism determined as per Chou-Talalay method. Results: Synergistic cytotoxicity was observed with reovirus and carfilzomib and perifisone in both reovirus resistant OPM2, KMS-11 or sensitive RPMI8226 cell lines. Interestingly, reovirus resistant cell lines demonstrated enhanced synergism in comparison to reovirus sensitive RPMI8226. Conclusion: Not all MM cell lines are amenable to reovirus mediated cell death. As phase II clinical trials for MM are currently underway this has important implications for the future use of reovirus as a therapeutic agent for cancer. The present study highlights the significance of preclinical studies in evaluating effective reovirus drug combinations for future use that could be extrapolated to a clinical setting. Currently we are also evaluating the effects of these drug combinations in vivo in a mouse model that represents the clinical scenario of MM. The mechanisms underlying the cytotoxicity mediated by reovirus and drug combinations is also being investigated at present. Understanding the signalling pathways of resistant tumor will help develop a more personalized approach of reovirus therapy for cancer patients in the future. Citation Format: Chandini M. Thirukkumaran, Zhong Qiao Shi, Paola Neri, Nizar Bahlis, Don Morris. Reovirus synergy with proteosome inhibitor carfilzomib and Akt inhibitor perifisone overcomes therapy resistance of multiple myeloma: promising preclinical activity. [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 1709. doi:10.1158/1538-7445.AM2014-1709