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Tasquinimod Is an A...
Tasquinimod Is an Allosteric Modulator of HDAC4 Survival Signaling within the Compromised Cancer Microenvironment
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Isaacs, John T. (author)
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Antony, Lizamma (author)
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Dalrymple, Susan L. (author)
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Brennen, W. Nathaniel (author)
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Gerber, Stephanie (author)
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Hammers, Hans (author)
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Wissing, Michel (author)
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Kachhap, Sushant (author)
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Luo, Jun (author)
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Xing, Li (author)
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Bjork, Per (author)
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Olsson, Anders (author)
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Bjork, Anders (author)
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- Leanderson, Tomas (author)
- Lund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups
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(creator_code:org_t)
- 2013
- 2013
- English.
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In: Cancer Research. - 1538-7445. ; 74:4, s. 1386-1399
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Abstract
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- Tasquinimod is an orally active antiangiogenic drug that is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer. However, the target of this drug has remained unclear. In this study, we applied diverse strategies to identify the histone deacetylase HDAC4 as a target for the antiangiogenic activity of tasquinimod. Our comprehensive analysis revealed allosteric binding (Kd 10-30 nmol/L) to the regulatory Zn2+ binding domain of HDAC4 that locks the protein in a conformation preventing HDAC4/N-CoR/HDAC3 complex formation. This binding inhibited colocalization of N-CoR/HDAC3, thereby inhibiting deacetylation of histones and HDAC4 client transcription factors, such as HIF-1 alpha, which are bound at promoter/enhancers where epigenetic reprogramming is required for cancer cell survival and angiogenic response. Through this mechanism, tasquinimod is effective as a monotherapeutic agent against human prostate, breast, bladder, and colon tumor xenografts, where its efficacy could be further enhanced in combination with a targeted thapsigargin prodrug (G202) that selectively kills tumor endothelial cells. Together, our findings define a mechanism of action of tasquinimod and offer a perspective on how its clinical activity might be leveraged in combination with other drugs that target the tumor microenvironment. Cancer Res; 73(4); 1386-99. (C) 2012 AACR.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Isaacs, John T.
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Antony, Lizamma
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Dalrymple, Susan ...
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Brennen, W. Nath ...
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Gerber, Stephani ...
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Hammers, Hans
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show more...
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Wissing, Michel
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Kachhap, Sushant
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Luo, Jun
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Xing, Li
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Bjork, Per
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Olsson, Anders
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Bjork, Anders
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Leanderson, Toma ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
- Articles in the publication
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Cancer Research
- By the university
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Lund University