Combination of Histone Deacetylase Inhibitor Panobinostat (LBH589) with β-Catenin Inhibitor Tegavivint (BC2059) Exerts Significant Anti-Myeloma Activity Both In Vitro and In Vivo

SIMPLE SUMMARY: Multiple myeloma remains an incurable malignancy with the majority of patients succumbing to the disease after receiving several lines of treatment, while acquiring drug resistance. Although panobinostat, a histone deacetylase inhibitor, has long been approved for the treatment of patients with relapsed/refractory myeloma it has not yet been incorporated into everyday practice. In this study we showed a significant synergistic anti-myeloma effect of low dose panobinostat and β-catenin inhibitor Tegavivint both in vitro and in vivo, with a favourable toxicity profile. This combination could significantly and safely benefit myeloma patients that have exhausted mainstream therapeutic modalities due to acquisition of drug resistance in the future. ABSTRACT: Over the last three decades changes in the treatment paradigm for newly diagnosed multiple myeloma (MM) have led to a significant increase in overall survival. Despite this, the majority of patients relapse after one or more lines of treatment while acquiring resistance to available therapies. Panobinostat, a pan-histone deacetylase inhibitor, was approved by the FDA in 2015 for patients with relapsed MM but how to incorporate panobinostat most effectively into everyday practice remains unclear. Dysregulation of the Wnt canonical pathway, and its key mediator β-catenin, has been shown to be important for the evolution of MM and the acquisition of drug resistance, making it a potentially attractive therapeutic target. Despite concerns regarding the safety of Wnt pathway inhibitors, we have recently shown that the β-catenin inhibitor Tegavivint is deliverable and effective in in vivo models of MM. In this study we show that the combination of low concentrations of panobinostat and Tegavivint have significant in vitro and in vivo anti-MM effects including in the context of proteasome inhibitor resistance, by targeting both aerobic glycolysis and mitochondrial respiration and the down-regulation of down-stream β-catenin targets including myc, cyclinD1, and cyclinD2. The significant anti-MM effect of this novel combination warrants further evaluation for the treatment of MM patients with relapsed and/or refractory MM.