Abstract 4701: Tasquinimod suppresses the adaptive stress response within sites of prostate cancer via disrupting zinc-dependent Histone Deacetylase 4 signaling.

Abstract

Abstract Tasquinimod (i.e., N-ethyl-N-phenyl-5-chloro-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-3-quinoline-carboxamide) is a novel orally active potent inhibitor of tumor angiogenesis with single agent efficacy which also enhances androgen ablation, taxane-based chemotherapies, or fractionated radiation in pre-clinical prostate cancer models [Expert Opin Investig Drugs (2010). 19: 1235-43]. Based upon its anti-angiogenic efficacy, tasquinimod is in clinical development and has successfully completed phase I/II testing and is presently in multi-center Phase III evaluation for the treatment of castration resistant prostate cancer at an oral dose of up to1mg per day. To clarify the molecular targets for tasquinimod's anti-angiogenic efficacy, a library of quinoline-3-carboxamide analogs was screened based upon inhibition of human endothelial cell sprouting in a 3-dimensional assay to identify the active pharmacophore. These structure activity relationship (SAR) studies document that the two carbonyl oxygens in the quinoline-2-position and 3-position carboxamide side chain are essential for activity. These SAR studies raised the issue of whether these two carbonyl oxygens might function in bidentate metal binding. To test this possibility surface plasmon resonance was used to evaluate binding of tasquinimod to Zn bound proteins. These studies document that tasquinimod binds with low nM affinity to Zn bound proteins. A combination of tumor, cell, and molecular biology assays identified HDAC4 as one of the Zn bound proteins to which tasquinimod binds. Using shRNA knock-down and subsequent replacement knock-in, both human prostate cancer cells and human endothelial cells require a critical level of nuclear HDAC4 function to survive in both cell culture and xenograft assays under cellular stress conditions like acidic pH and hypoxia characteristic of cancer growth. Survival under these stress conditions requires formation of HDAC4/N-CoR/HDAC3 complexes which bind to and deacetylate transcription factors, like HIF-1α, altering transcription. Such HDAC4/N-CoR/HDAC3 complex formation occurs through a structural Zn binding domain in HDAC4. While tasquinimod does not inhibit HDAC enzymatic activity directly, it binds HDAC4 and inhibits Zn-dependent formation of HDAC4/N-CoR/HDAC3 complex thus inhibiting deacetylation of HIF-1α preventing the adaptive transcription response needed for survival under acidic/hypoxia conditions. The fact that tasquinimod phenocopies the response of prostate cancer and endothelial cells to HDAC4 knock-down identifies HDAC4 as one of the critical targets for tasquinimod's mechanism of action. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4701. doi:1538-7445.AM2012-4701