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

Hay, Jodie F.; Lappin, Katrina; Liberante, Fabio; Kettyle, Laura M.; Matchett, Kyle B.; Thompson, Alexander; Mills, Ken I.

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.

Citation

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

• Journal Article Type: Article
• Acceptance Date: May 31, 2017
• Online Publication Date: Jul 1, 2017
• Publication Date: Sep 15, 2017
• Deposit Date: Feb 13, 2018
• Publicly Available Date: Feb 13, 2018
• Journal: Oncotarget
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 40
• DOI: https://doi.org/10.18632/oncotarget.18910
• Keywords: acute myeloid leukaemia, Vorinostat, HDAC, epigenetics
• Public URL: https://nottingham-repository.worktribe.com/output/882669
• Publisher URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620222/
• Contract Date: Feb 13, 2018