Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer

Abstract

Purpose VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic RCC. However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for both patients with TKI naïve or resistant RCC. Experimental design In this study, we performed transcriptome analysis of VEGFR TKI resistant tumors in a murine model and discovered that the SPHK/S1P pathway is upregulated at the time of resistance. We tested S1P pathway inhibition using an anti-S1P mAb (sphingomab), in two mouse xenograft models of RCC, and assessed tumor SPHK expression and S1P plasma levels in patients with metastatic RCC. Results Resistant tumors expressed several hypoxia regulated genes. The SPHK1 pathway was among the most highly upregulated pathways that accompanied resistance to VEGFR TKI therapy. SPHK1 was expressed in human RCC, and the product of SPHK1 activity, S1P, was elevated in patients with metastatic RCC suggesting that human RCC behavior could, in part, be due to over-production of S1P. Sphingomab neutralization of extracellular S1P slowed tumor growth in both mouse models. Mice bearing tumors that had developed resistance to sunitinib treatment also exhibited tumor growth suppression with sphingomab. Sphingomab treatment led to a reduction in tumor blood flow as measured by MRI. Conclusions Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment naïve RCC and also in the setting of resistance to VEGFR TKI therapy.

A phase 2 study of the sphingosine‐1‐phosphate antibody sonepcizumab in patients with metastatic renal cell carcinoma

“…In retrospect, early imaging may preclude ascertainment of a delayed response to therapy, which is particularly relevant if sonepcizumab activity is driven through the immune-mediated mechanisms described above. 9 Ultimately, however, there was no observed association between S1P level and clinical outcome. 6 A second issue that could have mitigated the observed PFS of sonepcizumab is the extent of prior therapies rendered.…”

“…2 The pivotal phase 3 studies leading to the approval of these agents document a progression-free survival (PFS) in the range of 9 months to 12 months with each agent. 9 In von Hippel-Lindau (VHL)-deficient RCC xenograft models (786-O and A498), transcriptomic analysis demonstrated the increased expression of sphingosine kinase 1 (SPHK1), which catalyzes S1P production, in resistant tumors. [6][7][8] Although these agents have bested therapies previously approved in this setting such as everolimus, to the best of our knowledge few patients are cured of their disease and PFS (in phase 3 studies) ranges from 4.5 to 7.5 months.…”

Distinct mechanisms of B and T lymphocyte accumulation generate tumor-draining lymph node hypertrophy

“…and Sphingomab 65 may be useful adjunctive antitumor therapies. Several mechanisms are implicated in the observed effects on tumor cells and cancer outcome, including regulation of new blood vessel formation, direct cellular toxicity, and regulation of cellular survival and metabolism 64,65 .…”

Newly-presented potential targeted drugs in the treatment of renal cell cancer

“…Zhang et al [37] have demonstrated that a sphingosine-1-phosphate (S1P) antibody induced S1P inhibition may be a new therapeutic strategy in patients with RCC and also in the batching of resistance to TKI therapy.…”