In patients with RCC, development of resistance after initial efficacy of inhibitors of the vascular endothelial growth factor (VEGF) pathway is common. In a new study, Liang Zhang and colleagues first demonstrated that sphingosine kinase 1 (Sphk1) transcription is upregulated in subcutaneous RCC xenografts in mice treated with sorafenib or sunitinib. In addition, using immunohistochemistry, they found that nine of 12 tumour samples from patients with clear cell RCC showed cytoplasmic expression of SPHK1, whereas proximal normal kidney tubules only showed faint expression. Furthermore, plasma levels of S1P were significantly higher in patients with RCC (n= 69) than in healthy volunteers (n= 28; P< 0.001).

Next, the team tested the effect of blocking S1P signalling using sphingomab in two xenograft mouse models of renal carcinoma. Tumour volumes in mice receiving vehicle only increased more quickly than tumour volumes in mice treated with sphingomab (P< 0.034 for 786-O cells and P< 0.040 for A498 cells). In 786-O xenografts, the average time until tumour volume increased by 75% was 8.5 days versus 17.5 days in vehicletreated mice and mice receiving 50 mg/kg sphingomab, respectively.