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

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.

S1P prophylaxis mitigates acute hypobaric hypoxia‐induced molecular, biochemical, and metabolic disturbances: A preclinical report

“…Although S1P‐mediated HIF‐1α accumulation has been reported several times, its mechanistic feasibility is still lacking . In our study, the S1P dose of 1 µg/kg b.w.…”

“…The cardioprotective consequences of S1P preconditioning, as well as its protective benefits in pulmonary/cerebral tissues, stem, at least in part, from induction HIF-1a and HSP 70 (7,10,(26)(27)(28). HIF-1a is a classical hypoxia-adaptive marker, functionally controlling the transcription of hypoxia-adaptive gene expression, including HSP70.…”

Inhibition of Sphingosine Phosphate Receptor 1 Signaling Enhances the Efficacy of VEGF Receptor Inhibition

“…A goal of our work has been to identify new endothelial-specific targets that can be rationally combined with VEGFR-targeted agents to improve their efficacy in inhibiting tumor angiogenesis. There is a well-characterized role for endothelial-specific S1PR1 signaling in angiogenesis (11)(12)(13)40) and well-known effects of tumor-specific SPHK1-HIF axis associated with resistance to VEGFR TKI therapy (9,16,18,41,42). Thus, we investigated whether targeting endothelial S1P1 signaling with Ex82 a potent, selective inhibitor of S1P1, may combine with VEGFR inhibition to target angiogenesis at two main pathways leading to greater reduction in tumor growth.…”

“…The combination of FTY720 with a VEGFR kinase inhibitor was shown to be additive, suggesting the potential for improving VEGF pathway-directed therapies. A monoclonal antibody specific for S1P (S1P mAb) also significantly inhibited tumor angiogenesis and growth in several animal models of human cancer (16)(17)(18). These effects were associated with inhibition of S1P-induced cancer cell proliferation and release of proangiogenic factors.…”

SphingomabTM, un anticorps anti-sphingosine 1-phosphate, comme agent anti-hypoxique dans le cancer

“…En amont, la voie de signalisation PI3K (inositol 1,4,5-trisphosphate 3-kinase)/Akt peut être induite par tous les récepteurs à S1P [15], suggérant que l'activation de la SphK1 en condition d'hypoxie peut être associée à une signalisation autocrine/paracrine de la S1P extracellulaire sécrétée par les cellules hypoxiques. Nos derniers résultats [16] démontrent que la neutralisation de la S1P extracellulaire, par le Sphingomab TM , diminue de façon significative l'accumulation de HIF-1 en conditions d'hypoxie, dans différentes lignées tumorales humaines (prostate, gliome, poumon). L'accumulation de HIF-1 en conditions d'hypoxie est bien la conséquence d'une sécrétion de S1P par les cellules hypoxiques, puisqu'une stratégie d'interférence ARN dirigée contre Spns2 (spinster homolog 2), un transporteur de la S1P, bloque également l'accumulation de HIF-1 en conditions d'hypoxie et que ceci peut être annulé par l'addition de S1P exogène.…”