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

223 Background: Hypoxia promotes vascularization, metastasis and resistance to treatments. The activation of HIF-1α is 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 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: Quantitation of hypoxia and angiogenesis, and treatment efficacy using an orthotopic (o.t) xenograft model of f...