Abstract
Alternative pathways to the 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 the VEGF and c-met pathways 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 resistant phenotype, we established an 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 antitumor 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.
Highlights
Renal cell carcinoma (RCC) strikes approximately >64,000 people and causes >13,000 deaths in a year in the United States [1]
80% of RCC cases are diagnosed as clear cell RCC and the majority of them are sporadic tumors with acquired defects in both alleles of VHL tumor-suppressor gene, resulting in VHL protein dysregulation [2]
To examine the therapeutic effect of axitinib and crizotinib in the high c-met–expressing 786-O model (Supplementary Fig. S1A), male SCID mice were orthotopically implanted under the kidney capsule with tumor tissues
Summary
Renal cell carcinoma (RCC) strikes approximately >64,000 people and causes >13,000 deaths in a year in the United States [1]. 80% of RCC cases are diagnosed as clear cell RCC (ccRCC) and the majority of them are sporadic tumors with acquired defects in both alleles of VHL (von Hippel-Landau) tumor-suppressor gene, resulting in VHL protein dysregulation [2]. This defective protein is unable to bind under hypoxic conditions, and trigger proteasome-mediated degradation of hypoxia-inducible transcription factor (HIF). The subsequent transcriptional hyperactivation of HIF-targeted genes, such as VEGF, platelet-derived growth factor (PDGF), TGFa, hepatocyte. This study was previously presented at the 2013 American Association for Cancer Research Annual Meeting.
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