Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy

Hay, J. F. , Lappin, K., Liberante, F., Kettyle, L. M., Matchett, K. B., Thompson, A. and Mills, K. I. (2017) Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy. Oncotarget, 8(40), pp. 67891-67903. (doi: 10.18632/oncotarget.18910) (PMID:28723639) (PMCID:PMC5620222)

Abstract

Several histone deacetylase inhibitors including Vorinostat have received FDA approval for the treatment of haematological malignancies. However, data from these trials indicate that Vorinostat has limited efficacy as a monotherapy, prompting the need for rational design of combination therapies. A number of epi-sensitised pathways, including sonic hedgehog (SHH), were identified in AML cells by integration of global patterns of histone H3 lysine 9 (H3K9) acetylation with transcriptomic analysis following Vorinostat-treatment. Direct targeting of the SHH pathway with SANT-1, following Vorinostat induced epi-sensitisation, resulted in synergistic cell death of AML cells. In addition, xenograft studies demonstrated that combination therapy induced a marked reduction in leukemic burden compared to control or single agents. Together, the data supports epi-sensitisation as a potential component of the strategy for the rational development of combination therapies in AML.

• Item Type: Articles
• Keywords: HDAC, vorinostat, acute myeloid leukaemia, epigenetics.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Hay, Dr Jodie
• Authors: Hay, J. F., Lappin, K., Liberante, F., Kettyle, L. M., Matchett, K. B., Thompson, A., and Mills, K. I.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Oncotarget
• Publisher: Impact Journals
• ISSN: 1949-2553
• ISSN (Online): 1949-2553
• Published Online: 01 July 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Oncotarget 8(40): 67891-67903
• Publisher Policy: Reproduced under a Creative Commons license