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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Vascular Endothelial Growth Factor (VEGF) pathway is crucial for tumor angiogenesis.
• Hepatocyte Growth Factor (HGF)/c-met pathway activation contributes to resistance against anti-VEGF therapies in cancer.
• Clear cell renal cell carcinoma (ccRCC) often involves dysregulation of these pathways.

Purpose of the Study:

• To evaluate the efficacy of combined VEGF and c-met pathway inhibition in ccRCC models.
• To assess the impact of this combination strategy on tumor growth, angiogenesis, and resistance.
• To explore the potential of this combination for both first- and second-line ccRCC treatment.

Main Methods:

• Utilized 786-O and patient-derived xenograft (RP-R-01) ccRCC models in SCID mice.
• Administered axitinib (VEGF receptor inhibitor) and crizotinib (c-met inhibitor) as single agents or in combination.
• Established a sunitinib-resistant ccRCC model to evaluate treatment efficacy in resistant phenotypes.

Main Results:

• Single-agent crizotinib reduced vascularization but did not inhibit tumor growth.
• Axitinib effectively inhibited angiogenesis and tumor growth in both sensitive and resistant models.
• Combination therapy with axitinib and crizotinib significantly enhanced antitumor effects and prolonged survival.
• The combination's efficacy was independent of c-met expression levels.

Conclusions:

• Combined blockade of VEGF and HGF/c-met pathways demonstrates significant antitumor activity in ccRCC.
• This combination strategy holds potential for treating ccRCC, including in cases of resistance to anti-VEGF therapies.
• Clinical investigation of combined VEGF and HGF/c-met pathway inhibition is warranted for ccRCC treatment.