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JAK1/2 and pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease

Evrot, Emeline and Ebel, Nicolas and Romanet, Vincent and Roelli, Claudia and Andraos-Rey, Rita and Qian, Zhiyan and Doelemeyer, Arno and Dammassa, Ernesta and Sterker, Dario and Hofmann, Francesco and Murakami, Masato and Baffert, Fabienne and Radimerski, Thomas (2013) JAK1/2 and pan-deacetylase inhibitor combination therapy yields improved efficacy in preclinical mouse models of JAK2V617F-driven disease. Clinical Cancer Research.

Abstract

JAK inhibitors have demonstrated rapid and durable reductions in splenomegaly, as well as improvement in symptoms and quality of life in patients with myelofibrosis. However, the impact on the mutant allele burden and bone marrow fibrosis has been modest, indicating that combinations with other agents may further improve outcomes. Histone deacetylase inhibition has emerged as a promising combination modality based on in vitro studies using JAK2V617F mutant models that suggested a synergistic effect upon combination with a JAK2 inhibitor, and encouraging single-agent activity of the pan-deacetylase inhibitor panobinostat in phase I/II myelofibrosis trials. Here, we investigated the combination of the JAK1/2 inhibitor ruxolitinib and panobinostat in mouse models of JAK2V617F-driven disease. The combination was found to have a more profound effect on efficacy readouts as compared to either agent alone, and the analysis of pharmacodynamic readouts demonstrated that ruxolitinib and panobinostat have non-overlapping and complementary effects on biological pathways.

Item Type: Article
Additional Information: The Article's title has changed, and I put the new title
Date Deposited: 04 May 2016 23:45
Last Modified: 04 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/11387

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