Inhibition of metastasis in a castration resistant prostate cancer model by the quinoline‐3‐carboxamide tasquinimod (ABR‐215050)
- 5 October 2011
- journal article
- research article
- Published by Wiley in The Prostate
- Vol. 72 (8), 913-924
- https://doi.org/10.1002/pros.21495
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. Prostate 72:913–924, 2012.Funding Information
- Swedish Cancer Society
- Swedish Research Council
- Sahlgrenska University Hospital
- Proliv Vast
- Swedish Johanniterhjälpen
- Swedish Medical Society
- Research Foundation of af Jochnick
- C. & S. Hagströmer
- A. Gabrielsson
- M. Bergvall
- Å. Wiberg
- H. Fries
This publication has 46 references indexed in Scilit:
- Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancerBritish Journal of Cancer, 2009
- Hypoxia-Induced Lysyl Oxidase Is a Critical Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic NicheCancer Cell, 2009
- Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 proteinThe Journal of Experimental Medicine, 2008
- Prostate cancerThe Lancet, 2008
- HIF1α Induces the Recruitment of Bone Marrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and InvasionCancer Cell, 2008
- Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasisNature, 2006
- Dissemination and growth of cancer cells in metastatic sitesNature Reviews Cancer, 2002
- Hypoxia — a key regulatory factor in tumour growthNature Reviews Cancer, 2002
- Multistep Nature of Metastatic Inefficiency: Dormancy of Solitary Cells after Successful Extravasation and Limited Survival of Early MicrometastasesThe American Journal of Pathology, 1998
- Tumor Angiogenesis: Therapeutic ImplicationsThe New England Journal of Medicine, 1971