Combination Strategy Targeting VEGF and HGF/c-met in Human Renal Cell Carcinoma Models

Abstract

Alternative pathways to the vascular endothelial grow factor (VEGF), such as hepatocyte growth factor or HGF/c-met, are emerging as key players in tumor angiogenesis and resistance to anti-VEGF therapies. The aim of this study was to assess the effects of a combination strategy targeting VEGF and c-met pathway in clear cell renal cell carcinoma (ccRCC) models. Male SCID mice (8/group) were implanted with 786-O tumor pieces and treated with either a selective VEGF receptor tyrosine kinase inhibitor, axitinib (36 mg/kg, 2×/day), a c-met inhibitor, crizotinib (25 mg/kg, 1×/day), or combination. We further tested this drug combination in a human ccRCC patient derived xenograft, RP-R-01, in both VEGF-targeted therapy sensitive and resistant models. To evaluate the resistance phenotype, we established RP-R-01 sunitinib resistant model by continuous sunitinib treatment (60 mg/kg, 1×/day) of RP-R-01 bearing-mice. Treatment with single agent crizotinib reduced tumor vascularization but failed to inhibit tumor growth in either model, despite also a significant increase of c-met expression and phosphorylation in the sunitinib resistant tumors. In contrast, axitinib treatment was effective in inhibiting angiogenesis and tumor growth in both models, with its anti-tumor effect significantly increased by the combined treatment with crizotinib, independently from c-met expression. Combination treatment also induced prolonged survival and significant tumor growth inhibition in the 786-O human RCC model. Overall, our results support the rationale for the clinical testing of combined VEGF and HGF/c-met pathway blockade in the treatment of ccRCC, both in first and second line setting.

Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma

“…One mechanism that has received considerable attention is redundancy in proangiogenic growth factor signaling (2,11,15,16). Human cancers, including RCC, express numerous additional proangiogenic factors, including fibroblast growth factor 2 (FGF2), hepatocyte growth factor (HGF), and IL8, which may stimulate the growth and survival of tumor blood vessels even when the VEGF-pathway is blocked (17)(18)(19)(20)(21)(22)(23)(24)(25). It may therefore be necessary to develop therapies that block the activity of multiple proangiogenic factors in these tumors.…”

Cabozantinib for the treatment of kidney cancer

“…In another study conducted in two animal models, one anti-VEGFR TKI (sunitinib) resistant and the other sensitive, combined blockade of both VEGF and HGF/MET pathways enhanced the anti-tumor effect in both models. This effect was found irrespective of MET expression [19]. In the same study it is worth noting that in sunitinib resistant model; MET expression was significantly increased, which highlights HGF/MET pathway as an important mechanism of resistance to antiangiogenesis therapy.…”

Postsorafenib systemic treatments for hepatocellular carcinoma: questions and opportunities after the regorafenib trial

“…As such, combined inhibition of the VEGFR and MET resulted in an increased efficacy compared with that achieved inhibiting either pathway alone in some tumor models [20][21][22][23].…”