Neutralizing S1P inhibits intratumoral hypoxia, induces vascular remodelling and sensitizes to chemotherapy in prostate cancer

// Isabelle Ader 1, 2, 3 , Cécile Gstalder 1, 2, 3, * , Pierre Bouquerel 1, 2, 3, * , Muriel Golzio 1, 2 , Guillaume Andrieu 1, 2, 3 , Santiago Zalvidea 5 , Sylvain Richard 5 , Roger A. Sabbadini 6 , Bernard Malavaud 1, 2, 3, 4 , Olivier Cuvillier 1, 2, 3 1 CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France 2 Université de Toulouse, UPS, IPBS, Toulouse, France 3 Equipe Labellisée Ligue Contre le Cancer, Toulouse, France 4 Hôpital Rangueil, Service d’Urologie et de Transplantation Rénale, Toulouse, France 5 INSERM U1046, Université Montpellier 1, Université Montpellier 2, CHU Arnaud de Villeneuve, Montpellier, France 6 Lpath Inc., San Diego, CA, USA * These authors have contributed equally to this work Correspondence to: Olivier Cuvillier, e-mail: olivier.cuvillier@ipbs.fr , olivier.cuvillier@inserm.fr Keywords: angiogenesis, hypoxia, sphingolipid, vessel normalization Received: December 01, 2014      Accepted: January 12, 2015      Published: January 29, 2015 ABSTRACT Hypoxia promotes neovascularization, increased tumor growth, and therapeutic resistance. The transcription factor, hypoxia-inducible factor 1α (HIF-1α), has been reported as the master driver of adaptation to hypoxia. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF-1α under hypoxia. Taking advantage of a monoclonal antibody neutralizing extracellular S1P (sphingomab), we report that inhibition of S1P extracellular signaling blocks HIF-1α accumulation and activity in several cancer cell models exposed to hypoxia. In an orthotopic xenograft model of prostate cancer, we show that sphingomab reduces hypoxia and modifies vessel architecture within 5 days of treatment, leading to increased intratumoral blood perfusion. Supporting the notion that a transient vascular normalization of tumor vessels is the mechanism by which sphingomab exerts its effects, we demonstrate that administration of the antibody for 5 days before chemotherapy is more effective at local tumor control and metastatic dissemination than any other treatment scheduling. These findings validate sphingomab as a potential new normalization agent that could contribute to successful sensitization of hypoxic tumors to chemotherapy.