658 patients with advanced RCC who had received at least one prior VEGFR tyrosine kinase inhibitor were randomised 1:1 to cabozantinib (60 mg daily) or everolimus (10 mg daily).
Renal cell carcinoma (RCC) is highly dependent on angiogenesis, due to the overactivation of the VHL/HIF/VEGF/VEGFRs axis; this justifies the marked sensitivity of this neoplasm to antiangiogenic agents which, however, ultimately fail to control tumor growth.
Addressing the best treatment for non-clear cell renal cell carcinoma: A meta-analysis of randomised clinical trials comparing VEGFR-TKis versus mTORi-targeted therapies.
Axitinib is an approved drug that targets the vascular endothelial growth factor receptor 2 (VEGFR2) and is licensed for second-line therapy of renal cell carcinoma.
Beyond well-validated signaling targets such as VHL, VEGFR and mTOR, additional pathways including HGF/c-MET and Wnt/β-catenin have emerged as important to RCC pathogenesis.
Finally, we used a coculture model of human umbilical vein endothelial cells with RCC cell lines to find out that HMGB1 also increased the expression of VEGF and VEGFR2 in human umbilical vein endothelial cells.
Furthermore, since VEGFR-1 and VEGFR-2 proteins were expressed in the tumor cells as well as in the endothelial cells, these receptors may also be responsible for the progression of RCC.
In the phase III METEOR trial, tyrosine kinase inhibitor cabozantinib significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival compared to everolimus in patients with advanced renal cell carcinoma (RCC) who had received prior VEGFR inhibitor therapy.
In this study, VEGFR-2 antibody (DC101) inhibited growth of RenCa renal cell carcinoma lung metastases by 26%, whereas VEGFR-1 antibody (MF-1) had no effect.
It drives tumorigenesis by activating downstream hypoxia responsive genes and proangiogenic factors like VEGFR, and is responsible for the activity of tyrosine kinase inhibitors in RCC.
It has recently been approved by the European Medicines Agency (EMA) for first-line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mammalian target of rapamycin (mTOR) pathway inhibitor-naive, following disease progression after one prior treatment with cytokine therapy for advanced RCC.
Microarray expression profiling and Western blot analysis revealed that among known sunitinib targets, only platelet-derived growth factor receptor-beta and vascular endothelial growth factor receptor-2 (VEGFR-2) were overexpressed in ccRCCs relative to normal tissues.
Nivolumab has emerged as a promising new therapy in advanced malignancies, and the first agent to show survival advantage in patients failing prior VEGFR-targeted therapy in metastatic RCC.
Our data have important implications for combination therapy design, supporting the conclusion that targeting VEGFR2 alone in RCC has the potential to have pleiotropic effects on tumor stroma.
Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment-naïve RCC and also in the setting of resistance to VEGFR TKI therapy.
Over the past decade, therapies targeting the VEGF/VEGFR and mTOR pathways have served as the standard of care for the clinical management of renal cell carcinoma (RCC) patients.
RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs.
Structure-Based Virtual Screening for the Identification of High Affinity Compounds as Potent VEGFR2 Inhibitors for the Treatment of Renal Cell Carcinoma.