Abstract 4311: Utilising the preclinical Vk*MYC model of multiple myeloma to rapidly and effectively screen novel therapies and their combinations

Abstract

Abstract Introduction: Multiple myeloma (MM) is an incurable hematological neoplasm with an unmet need for novel therapeutic options. Here we employed the genetically tractable Vk*MYC murine model of MM to screen current and novel therapeutics in transgenic Vk*MYC mice and in transplant models of Vk*MYC MM. In addition to assessing single agent activity we also determined the effects of the histone-deacetylase inhibitor (HDACi) panobinostat (LBH-589) with the proteosome inhibitor bortezomib (Velcade) used in combination. Methods: Current and novel anti-MM agents (32) were screened in transgenic Vk*MYC mice (≥60wk) using clinically based regimens. Of these, panobinostat and bortezomib were shown to be the most efficacious and were selected to treat immunocompetent C57BL/6 mice bearing transplanted Vk*MYC MM (2 months post-transplant). Combination therapy was investigated in transplanted Vk*MYC MM consisting of low dose panobinostat (10mg/kg) with bortezomib (0.5mg/kg). Serum paraprotein levels were measured in all mice. Tumour load, drug targets and apoptosis were assessed by FACS or IHC staining of bone marrow sections. Results: Initial drug screening in Vk*MYC transgenic mice demonstrated anti-MM activity of panobinostat and bortezomib reflected by 50 and >25% reductions from baseline paraprotein levels, respectively. Similarly, serum paraprotein in C57BL/6 mice bearing Vk*MYC MM was significantly reduced with panobinostat (25mg/kg, 4d; 15mg/kg 5d/wk, 3wk) and bortezomib (0.5mg/kg, every 4d) alone compared with vehicle-treated mice. Moreover, panobinostat induced a significant survival advantage compared with vehicle (36.5d vs. 16d, p<0.01). Combination therapy using panobinostat and bortezomib at low doses reduced paraprotein significantly more than either agent alone. This was associated with histone-H3 acetylation, apoptosis induction and a reduction in viable plasma cells within bone marrow. Conclusions: These results suggest that panobinostat and bortezomib have single agent activity against MM and are the first to demonstrate therapeutic benefit in the pre-clinical Vk*MYC MM model. Moreover, combination therapies of panobinostat with proteosome inhibitors may be a rational approach for the treatment of MM. Future studies will investigate the molecular events underlying the single agent and combination effects of panobinostat and bortezomib using the Vk*MYC MM model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4311. doi:10.1158/1538-7445.AM2011-4311