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: Karin Jennbacken, Karin Welén, Anders Olsson, Bengt Axelsson, Marie Törngren, Jan-Erik Damber, Tomas Leanderson
• Journal: The Prostate (Prostate) Vol. 72 Issue 8 Pg. 913-24 (Jun 01 2012) ISSN: 1097-0045 [Electronic] United States
• PMID: 22287276 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• Angiogenesis Inhibitors
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Quinolines
• Quinolones
• SPZ1 protein, human
• tasquinimod

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
• Cell Line, Tumor
• Down-Regulation
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Male
• Mice
• Mice, Nude
• Neoplasm Metastasis (drug therapy)
• Orchiectomy
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Quinolines (therapeutic use)
• Quinolones
• Treatment Outcome
• Up-Regulation
• Xenograft Model Antitumor Assays