Effect of a therapeutic sphingosine 1-phosphate antibody on intratumoral hypoxia and sensitivity to standard chemotherapy in prostate cancer animal model.

Abstract

24 Background: Hypoxia promotes neovascularization, metastasis, growth and resistance to treatments. The activation of 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 (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 up-regulated under hypoxia, may help normalizing the tumor 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: Quantitation of hypoxia and angiogenesis, and treatment efficacy using an orthotopic (o.t) xenograft model of fluorescent HRPC cells. Results: We provide in vitro evidence that inhibiting 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 hypoxia. Second, using an o.t model of prostate cancer, we show that an anti-S1P antibody inhibits intratumoral hypoxia and modifies vessel architecture within 5 days of treatment. Third, we demonstrate that an anti-S1P strategy sensitizes to docetaxel, the “gold standard” treatment for HRPC. 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 antibodytogether withdocetaxel was not only accompanied by a smaller primary tumor volume compared to docetaxel alone, but also significantly reduced the occurrence and number of metastases. Conclusions: These data establish the proof-of-concept that blocking the exogenous action of S1P reduces intratumoral hypoxia and sensitizes to chemotherapy in prostate cancer animal model. [Table: see text]