PO-455 Epigenetic insights: resminostat regulates targets associated with the pathogenesis of cutaneous T cell lymphoma (CTCL)

Abstract

IntroductionCutaneous T cell lymphoma (CTCL) is a heterogeneous group of extra-nodal non-Hodgkin lymphomas arising from transformation and clonal expansion of skin-homing T cells. Epigenetics alterations have been described for the molecular pathogenesis of CTCL. Resminostat is a potent, orally bioavailable histone deacetylase (HDAC) inhibitor targeting class I, IIb and IV and is currently in phase II of clinical development. Resminostat showed anti-tumoral in vitro efficacy by inhibiting proliferation of CTCL cell lines. The aim of this study was to elucidate resminostat’s molecular mechanism of action in CTCL using a genome-wide approach.Material and methodsResminostat’s mechanism of action was analysed using a set of established CTCL cell lines representing different types of CTCL. Global lysine acetylation was evaluated by flow cytometry and specific histone H3 acetylation at lysine residue 27 (H3K27ac) was mapped genome-widely by chromatin immunoprecipitation followed by sequencing (ChIP-seq). Resminostat’s effect on global gene expression was analysed by RNA-seq focusing on CTCL-relevant pathways and genes.Results and discussionsResminostat increased total lysine acetylation in CTCL cell lines. The active epigenetic mark H3K27ac dose-dependently accumulated on a genome-wide level as detected by ChIP-seq analysis. Global gene expression profiling revealed both gene induction and repression by resminostat. First data showed a regulation of T helper (Th) 1 and 2 specific genes implying that resminostat normalises the Th1/Th2 imbalance in CTCL which is discussed to be associated with disease progression. Moreover, expression of skin-homing receptor genes was reduced by resminostat indicating a potential effect of resminostat on the cutaneous tropism of malignant T cells. Furthermore, the pruritus mediator IL-31 was downregulated by resminostat suggesting an attenuation of itching and thus indicating an important benefit for CTCL patients regarding their health-related quality of life.ConclusionFirst results from a genome-wide study suggest a promising impact of resminostat on different targets relevant for the pathogenesis of CTCL. These data broaden our understanding of resminostat’s molecular mechanism of action in CTCL and support our current clinical phase II trial evaluating resminostat for maintenance treatment of patients with advanced stage CTCL (RESMAIN, NCT02953301).