Abstract LB-35: A monoclonal sphingosine 1-phosphate antibody inhibits intratumoral hypoxia and sensitizes to docetaxel in prostate cancer animal model

Abstract

Abstract The reduction in the normal level of tissue oxygen tension or hypoxia is a characteristic of solid tumors that triggers the activation of signaling pathways promoting neovascularization, metastasis, increased tumor growth, and resistance to treatments. The activation of the transcription factor hypoxia-inducible factor 1α (HIF-1α) has been identified as the master mechanism of adaptation to hypoxia. In a recent study (Ader et al, Cancer Res, 2008), we identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway, which elicits various cellular processes including cell proliferation, cell survival, or angiogenesis, as a new modulator of HIF-1α activity under hypoxic conditions Indeed, we have shown that SphK1 activity (which generates S1P) was rapidly stimulated under low oxygen conditions. The pharmacological inhibition and RNA silencing of SphK1 activity could prevent the accumulation of HIF-1α and its transcriptional activity in multiple cancer cell lineages - including prostate - suggesting a canonical pathway. We have suggested that inhibiting the SphK1/S1P signaling, that is up-regulated under low oxygen tension, might help normalizing the tumor microenvironment and increase tumor sensitivity to radiation and chemotherapy, in the broader concept of « normalization of tumor vessels » as tumor oxygenation is known to enhance response to chemotherapy and radiation (reviewed in Ader et al., Cancer Res, 2009). S1P is believed to exert most of its actions as a specific ligand for a family of five cognate G protein-coupled receptors to elicit paracrine or autocrine signaling cascades. We now provide 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 transcriptional activity in prostate cancer cells exposed to hypoxia. More importantly, in an orthotopic (o.t) xenograft model of prostate cancer, we show that a monoclonal antibody directed against S1P markedly reduces intratumoral hypoxia and modifies vessel architecture within 5 days of treatment. Finally, we demonstrate for the first time that a monoclonal antibody directed against S1P could sensitize to the antitumoral effects of docetaxel, the ‘gold standard’ treatment for hormone-refractory prostate cancer. Indeed, a 5-day anti-S1P antibody pretreatment markedly sensitizes to docetaxel in an o.t. PC-3/green fluorescent protein 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 markedly reduced the occurrence and number of metastases. In conclusion, these data establish the proof-of-concept that blocking the exogenous action of S1P, by reducing intratumoral hypoxia, can sensitize to docetaxel-based chemotherapy in prostate cancer animal model. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-35.