title: Tasquinimod Is an Allosteric Modulator of HDAC4 survival signaling within the compromised cancer microenvironment.
abstract: 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 Zn(2+) 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-1α, 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. ©2012 AACR.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University, 1650 Orleans St., Baltimore, MD 21287, USA. isaacjo@jhmi.edu
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.forename: Lizamma
authors.initials: L
authors.lastname: Antony
authors.forename: Susan L
authors.initials: SL
authors.lastname: Dalrymple
authors.forename: W Nathaniel
authors.initials: WN
authors.lastname: Brennen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gerber
authors.forename: Hans
authors.initials: H
authors.lastname: Hammers
authors.forename: Michel
authors.initials: M
authors.lastname: Wissing
authors.forename: Sushant
authors.initials: S
authors.lastname: Kachhap
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Per
authors.initials: P
authors.lastname: Björk
authors.forename: Anders
authors.initials: A
authors.lastname: Olsson
authors.forename: Anders
authors.initials: A
authors.lastname: Björk
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000494:Allosteric Regulation; D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011355:Prodrugs / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000494:pharmacology*; D015363:Quinolones; D034622:RNA Interference; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019284:Thapsigargin / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C497442:HIF1A protein, human; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011355:Prodrugs; D011804:Quinolines; D015363:Quinolones; D012097:Repressor Proteins; D019284:Thapsigargin; C516109:tasquinimod; C400300:HDAC4 protein, human; D006655:Histone Deacetylases