Abstract
Abstract Renal clear cell carcinoma (RCC) is the most common type of kidney cancer in adults and represents 80% of cases. At the time of diagnosis, approximately 30% of patients have distant metastases. In addition, one third of patients who have surgical resection of the primary tumor eventually relapse and develop metastases. Effective agents that help to prevent the development of metastatic RCC are not available. Tasquinimod is a novel agent in clinical development for metastatic castration-resistant prostate cancer that has been shown to have immunomodulatory, anti-angiogenic, and anti-metastatic properties. In the current study, we tested whether tasquinimod effectively inhibits local invasion and spontaneous lung metastases in RCC. Two preclinical mouse models of RCC were used for this purpose: a xenograft nude model A498 and a recently established patient-derived xenograft model, RP-R-02 LM. In both models, tasquinimod had a modest effect on the growth of the primary tumors implanted subcutaneously. Interestingly, in the A498 RCC model, gene expression analysis in tumors revealed that tasquinimod increased E-cadherin and decreased vimentin expression, suggesting an effect on reversal of epithelial-mesenchymal transition. In addition, tasquinimod significantly decreased CXCR4 expression, suggesting a reduction in invasiveness and metastatic phenotype. To further test this hypothesis, we used the RP-R-02 LM model that is able to develop lung metastases. Tasquinimod induced a 66% reduction of lung metastases in comparison with the control group (p<0.01). Following tasquinimod treatment CD206+/Arginase 1+/high suppressive M2-polarized infiltrating macrophages were decreased in primary tumors, but even more so in the lung parenchyma and tumor nodules. In summary, our results demonstrate that tasquinimod has immunomodulatory and anti-metastatic properties in RCC models, providing a biological rationale for the clinical assessment of tasquinimod in RCC patients. Citation Format: Li Shen, Valerie Pierron, Anne-Laure Bauchet, Jessica Nakhle, Ashley Orillion, Remi Adelaiye, Eric Ciamporcero, Florence Meyer-Losic, Helena Eriksson, Nathalie Lassau, Ingrid Leguerney, Fabien Schmidlin, Anders Olsson, Roberto Pili. Tasquinimod inhibits local invasion and metastases in two preclinical models of renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4120. doi:10.1158/1538-7445.AM2015-4120
Published Version
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