Résumé
Hypoxia promotes neovascularization, metastasis, and resistance to treatments. The activation of the transcription factor HIF-1α has been identified as the master mechanism of adaptation to hypoxia. We recently identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α activity under hypoxia in multiple cancer cell models including prostate cancer (Ader et al, Cancer Res, 2008). S1P elicits proliferation, survival, or angiogenesis, and is believed to exert most of its actions as a ligand for a family of specific GPCRs to elicit paracrine or autocrine signaling. We have suggested that inhibiting SphK1/S1P signaling, which is upregulated under hypoxia, may normalize the microenvironment and increase sensitivity to chemotherapy, in the broader concept of “normalization of tumor vessels” as tumor oxygenation is known to enhance response to chemotherapy (Ader et al., Cancer Res, 2009). Methods: Quantification of intratumoral hypoxia and angiogenesis, and treatment efficacy (primary tumor, metatasis dissemination) using an orthotopic (o.t) xenograft model of fluorescent hormone refractory prostate cancer cells. Results: We first provide in vitro evidence that inhibition of the S1P exogenous signaling, through pharmacological inhibition of its receptors or by taking advantage of a monoclonal antibody neutralizing S1P, blocks HIF-1α accumulation and its activity in prostate cancer cells under to hypoxia. Second, using an o.t model of prostate cancer, we show that an anti-S1P antibody inhibits intratumoral hypoxia and modifies vessel architecture and improves tumor perfusion within 5 days of treatment. Third, we show for the first time that an anti-S1P strategy sensitizes to docetaxel, the ‘gold standard’ treatment for hormone-refractory prostate cancer. A 5-day anti-S1P antibody pretreatment markedly sensitizes to docetaxel in an o.t. PC-3/GFP model established in nude mice. The combination anti-S1P antibody together with docetaxel was not only accompanied by a smaller primary tumor volume compared to docetaxel treatment, but also significantly reduced the occurrence and number of metastases. Conclusion: These preclinical data establish the proof-of-concept that blocking the exogenous action of S1P induces vascular normalization, improves intratumoral oxygenation and sensitizes to chemotherapy in prostate cancer animal model. Citation Format: Authors. Abstract title [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4826. doi:1538-7445.AM2012-4826