Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models.
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.
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York. Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Eric
E
Ciamporcero
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
Kiersten Marie
KM
Miles
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York. Department of Cancer Pathology and Prevention, Roswell Park Cancer Institute, Buffalo, New York.
Remi
R
Adelaiye
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York. Department of Cancer Pathology and Prevention, Roswell Park Cancer Institute, Buffalo, New York.
Swathi
S
Ramakrishnan
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York.
Li
L
Shen
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York. Department of Cancer Pathology and Prevention, Roswell Park Cancer Institute, Buffalo, New York.
ShengYu
S
Ku
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Stefania
S
Pizzimenti
Department of Anatomy, Comprehensive Cancer Center, Cardiovascular Research Institute, University of California-San Francisco, San Francisco, California.
Barbara
B
Sennino
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Giuseppina
G
Barrera
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, New York. Roberto.Pili@RoswellPark.org.
Roberto
R
Pili
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D007191:Indazoles / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077547:Crizotinib; D000077784:Axitinib; D019859:Proto-Oncogene Proteins c-met; D000077210:Sunitinib