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

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

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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-sensitization, 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
Original languageEnglish
Pages (from-to)67891-67903
Number of pages13
JournalOncotarget
Volume8
Issue number40
DOIs
Publication statusPublished - 01 Jul 2017

Keywords

  • acute myeloid leukaemia
  • Vorinostat
  • HDAC
  • epigenetics

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