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

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Jodie F Hay1,2, Katrina Lappin1, Fabio Liberante1,3

  • 1Blood Cancer Research Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.

Oncotarget
|October 6, 2017
PubMed

Insights

Combining Vorinostat with SHH pathway inhibition synergistically kills acute myeloid leukemia (AML) cells. This combination therapy significantly reduces leukemia burden, offering a promising strategy for AML treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Histone deacetylase inhibitors like Vorinostat are approved for hematological malignancies.
  • Vorinostat shows limited efficacy as a monotherapy, necessitating combination strategies.
  • Acute myeloid leukemia (AML) requires novel therapeutic approaches.

Purpose of the Study:

  • To investigate combination therapies for AML by targeting epi-sensitized pathways.
  • To evaluate the efficacy of Vorinostat combined with sonic hedgehog (SHH) pathway inhibition in AML.

Main Methods:

  • Integration of histone acetylation patterns and transcriptomic analysis to identify Vorinostat-induced epi-sensitized pathways.
  • Treatment of AML cells with Vorinostat followed by SHH pathway inhibitor (SANT-1).
  • In vitro cell death assays and in vivo xenograft studies in mouse models.

Main Results:

  • Vorinostat treatment sensitized AML cells to SHH pathway targeting.
  • Combination therapy with Vorinostat and SANT-1 resulted in synergistic cell death of AML cells.
  • Xenograft studies showed a marked reduction in leukemic burden with combination therapy compared to single agents.

Conclusions:

  • Epi-sensitization is a viable strategy for rational combination therapy design in AML.
  • The combination of Vorinostat and SHH pathway inhibition demonstrates significant anti-leukemic activity.
  • Targeting epi-sensitized pathways offers a promising avenue for overcoming Vorinostat resistance in AML.
Keywords:
HDACVorinostatacute myeloid leukaemiaepigenetics

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