title: Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment.
abstract: Tasquinimod, an orally active quinoline-3-carboxamide, binds with high affinity to HDAC4 and S100A9 in cancer and infiltrating host cells within compromised tumor microenvironment inhibiting adaptive survival pathways needed for an angiogenic response. Clinical trials document that as low as 0.5-1mg tasquinimod/day is therapeutic against castrate resistant metastatic prostate cancer. Tasquinimod is metabolized via cytochrome P4503A4, but ketoconazole at a dose which completely inhibits CYP3A metabolism does not affect tasquinimod's ability to inhibit endothelial "sprouting" in vitro or anti-cancer efficacy against human prostate cancer xenografts in vivo. Tasquinimod's potency is facilitated by its reversible binding (Kd < 35 μM) to the IIA subdomain of albumin (Sudlow's site I). As blood vessels within the compromised cancer microenvironment are characterized by a higher degree of leakiness than those in normal tissues, this results in an enhanced uptake of tasquinimod bound to albumin in cancer tissue via a tumor specific process known as the "enhanced permeability and retention" (i.e., EPR) effect. Thus, despite plasma levels of < 1 µM, the EPR effect results in intracellular drug concentrations of 2-3 µM, levels several-fold higher than needed for inhibition of endothelial sprouting (IC50 ~ 0.5 µM) or for inhibition of HDAC4 and S100A9 mediated tumor growth.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ,Baltimore, MD; The Brady Urological Institute-Department of Urology, The Johns Hopkins University School of Medicine ,Baltimore, MD.
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ,Baltimore, MD.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Dalrymple
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ,Baltimore, MD.
authors.forename: D Marc
authors.initials: DM
authors.lastname: Rosen
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ,Baltimore, MD.
authors.forename: Hans
authors.initials: H
authors.lastname: Hammers
authors.affiliation: Active Biotech, AB Lund, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Olsson
authors.affiliation: Active Biotech, AB Lund, Sweden; Immunology group, Lund University, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009919:Orchiectomy; D064129:Prostatic Neoplasms, Castration-Resistant / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015363:Quinolones; D012709:Serum Albumin / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D011804:Quinolines; D015363:Quinolones; D012709:Serum Albumin; C516109:tasquinimod