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

Hay, Jodie F. and Lappin, Katrina and Liberante, Fabio and Kettyle, Laura M. and Matchett, Kyle B. and Thompson, Alexander and Mills, Ken I. (2017) Integrated analysis of the molecular action of Vorinostat identifies epi-sensitised targets for combination therapy. Oncotarget, 8 (40). pp. 67891-67903. ISSN 1949-2553

[img]
Preview
PDF - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Available under Licence Creative Commons Attribution.
Download (5MB) | Preview

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: Article
Keywords: acute myeloid leukaemia, Vorinostat, HDAC, epigenetics
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Medicine > Division of Cancer and Stem Cells
Identification Number: 10.18632/oncotarget.18910
Depositing User: Eprints, Support
Date Deposited: 13 Feb 2018 09:52
Last Modified: 14 Feb 2018 04:43
URI: http://eprints.nottingham.ac.uk/id/eprint/49754

Actions (Archive Staff Only)

Edit View Edit View