Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models

Eric Ciamporcero, Kiersten Marie Miles, Remi Adelaiye, Swathi Ramakrishnan, Li Shen, Sheng Yu Ku, Stefania Pizzimenti, Barbara Sennino, Giuseppina Barrera, Roberto Pili

Research output: Contribution to journalArticle

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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, 2x/day); a c-met inhibitor, crizotinib (25 mg/kg, 1x/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, 1x/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.

Original languageEnglish (US)
Pages (from-to)101-110
Number of pages10
JournalMolecular Cancer Therapeutics
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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Renal Cell Carcinoma
Vascular Endothelial Growth Factor A
Neoplasms
Therapeutics
Growth
Vascular Endothelial Growth Factor Receptor
Hepatocyte Growth Factor
SCID Mice
Drug Combinations
Heterografts
Protein-Tyrosine Kinases
Phosphorylation
Phenotype
Survival
crizotinib
sunitinib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models. / Ciamporcero, Eric; Miles, Kiersten Marie; Adelaiye, Remi; Ramakrishnan, Swathi; Shen, Li; Ku, Sheng Yu; Pizzimenti, Stefania; Sennino, Barbara; Barrera, Giuseppina; Pili, Roberto.

In: Molecular Cancer Therapeutics, Vol. 14, No. 1, 01.01.2015, p. 101-110.

Research output: Contribution to journalArticle

Ciamporcero, E, Miles, KM, Adelaiye, R, Ramakrishnan, S, Shen, L, Ku, SY, Pizzimenti, S, Sennino, B, Barrera, G & Pili, R 2015, 'Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models', Molecular Cancer Therapeutics, vol. 14, no. 1, pp. 101-110. https://doi.org/10.1158/1535-7163.MCT-14-0094
Ciamporcero, Eric ; Miles, Kiersten Marie ; Adelaiye, Remi ; Ramakrishnan, Swathi ; Shen, Li ; Ku, Sheng Yu ; Pizzimenti, Stefania ; Sennino, Barbara ; Barrera, Giuseppina ; Pili, Roberto. / Combination strategy targeting VEGF and HGF/c-met in human renal cell carcinoma models. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 1. pp. 101-110.
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