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Tasquinimod Is an Allosteric Modulator of HDAC4 survival signaling within the compromised cancer microenvironment

John T Isaacs1, Lizamma Antony, Susan L Dalrymple

  • 1Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21287, USA. isaacjo@jhmi.edu

Cancer Research
|November 15, 2012
PubMed

Insights

Tasquinimod targets histone deacetylase HDAC4, inhibiting cancer cell survival and angiogenesis. This antiangiogenic drug

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cancer Research

Background:

  • Tasquinimod is an oral antiangiogenic drug in Phase III trials for castration-resistant prostate cancer.
  • The precise molecular target of tasquinimod's antiangiogenic activity remained unidentified.

Purpose of the Study:

  • To identify the molecular target responsible for tasquinimod's antiangiogenic effects.
  • To elucidate the mechanism of action of tasquinimod.

Main Methods:

  • Diverse biochemical and cellular assays were employed.
  • Allosteric binding studies to identify target interaction.
  • Analysis of protein complex formation and histone deacetylation.
  • In vivo xenograft studies in mouse models.

Main Results:

  • Histone deacetylase HDAC4 was identified as a direct target of tasquinimod.
  • Tasquinimod allosterically binds to HDAC4, preventing the formation of the HDAC4/N-CoR/HDAC3 complex.
  • This inhibition disrupts histone deacetylation and downregulates pro-angiogenic factors like HIF-1α.
  • Tasquinimod demonstrated efficacy against various tumor xenografts and enhanced efficacy with G202.

Conclusions:

  • Tasquinimod's antiangiogenic mechanism involves the inhibition of HDAC4.
  • This action impacts epigenetic reprogramming crucial for tumor survival and angiogenesis.
  • Findings support combination therapies targeting the tumor microenvironment.

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