title: Inhibition of metastasis in a castration resistant prostate cancer model by the quinoline-3-carboxamide tasquinimod (ABR-215050).
abstract: BACKGROUND
  Tasquinimod (ABR-215050) is an orally active quinoline-3-carboxamide analog that has completed phase II clinical trial in patients with castration resistant prostate cancer, showing promising inhibiting effects on the occurrence of metastasis and delayed disease progression. Its mechanism of action is not fully elucidated, but previous studies show anti-angiogenic effects and strong interaction with the S100A9 protein.
  
  
  METHODS
  This study was performed to evaluate if tasquinimod inhibits prostate cancer metastasis, by using both orthotopic and intratibial xenograft models. Animals were treated with tasquinimod, and tumor growth characteristics as well as molecular markers for metastasis and angiogenesis were analyzed.
  
  
  RESULTS
  The results show that formation of lung and lymph node metastases from orthotopic castration resistant prostate tumors was inhibited by tasquinimod treatment. Importantly, establishment of tumors in the bone after intratibial implantation was suppressed by tasquinimod. In addition, establishment and growth of subcutaneous tumors were affected. Both in primary tumors and serum from treated mice an upregulation of thrombospondin 1 was observed. Further, downregulation of the hypoxia driven genes VEGF, CXCR4, and LOX was detected in the primary tasquinimod-treated tumors and decreased expression of chemotactic ligand SDF-1 was demonstrated in the lungs. Thus, these molecular changes could contribute to the anti-angiogenic and anti-metastatic effects of tasquinimod.
  
  
  CONCLUSIONS
  In conclusion, this study and clinical data show that tasquinimod interferes with the metastatic process, presumably by inhibition of tumor establishment. Therefore, tasquinimod is an interesting treatment option for patients with prostate cancer prone to metastasis.
authors.affiliation: Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Box 425, 40530 Göteborg, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Jennbacken
authors.forename: Karin
authors.initials: K
authors.lastname: Welén
authors.forename: Anders
authors.initials: A
authors.lastname: Olsson
authors.forename: Bengt
authors.initials: B
authors.lastname: Axelsson
authors.forename: Marie
authors.initials: M
authors.lastname: Törngren
authors.forename: Jan-Erik
authors.initials: JE
authors.lastname: Damber
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011804:Quinolines / Q000627:therapeutic use*; D015363:Quinolones; D016896:Treatment Outcome; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011804:Quinolines; D015363:Quinolones; C481348:SPZ1 protein, human; C516109:tasquinimod