Vascular Endothelial Growth Factor–Targeted Therapies in Advanced Renal Cell Carcinoma
Section snippets
Von Hippel-Lindau and VEGF
First isolated in the hereditary syndrome Von Hippel-Lindau (VHL) disease, the importance of the VHL tumor-suppressor gene emerged in sporadic clear cell RCC.1, 2, 3 VHL gene inactivation has been observed in 84% to 98% of sporadic RCCs.4, 5, 6 These observations are specific to clear cell RCC histology; VHL mutations have not been observed in other subtypes of RCC. Biallellic VHL gene inactivation has, therefore, been considered a key event in clear cell RCC oncogenesis according to the
Bevacizumab
Bevacizumab (Avastin, Genentech, South San Francisco, CA, USA) is a recombinant monoclonal antibody (mAb) IgG1 antibody that has been developed for humans from murine anti-VEGF mAb A4.6.1. The murine mAb A4.6.1 is specific for human VEGF, binding to all of the known isoforms of the ligand (eg, VEGF121, VEGF165, VEGF181, VEGF206). It is formed through alternative gene splicing, preventing it from binding to VEGFRs on vascular endothelial cells. In 1997, murine anti-VEGF mAb A4.6.1 was adapted
VEGFR tyrosine kinase inhibitors
Better understanding of the biology of VEGF and its related pathway in the pathogenesis of RCC led to the era of small molecule tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib, and axitinib and tivozanib, which are currently being evaluated), which block the intracellular domain of the VEGFR, in the management of RCC.
Summary
VEGF targeted therapy is the main treatment of mRCC in 2011. Both selective VEGF blockade using bevacizumab and VEGF receptor inhibition are effective and have almost similar activities, but have different potencies (Tables 3 and 4) and toxicity profiles (Table 5). Off-target effects are important to consider for treatment decisions, and ongoing and future studies will be critical for choosing between currently available drugs (bevacizumab, sorafenib, sunitinib, pazopanib) and upcoming new
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Cited by (43)
Pyridine ring as an important scaffold in anticancer drugs
2022, Recent Developments in the Synthesis and Applications of PyridinesMicroRNA-185 inhibits cell proliferation and induces cell apoptosis by targeting VEGFA directly in von Hippel-Lindau-inactivated clear cell renal cell carcinoma
2015, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :The well-recognized result of VHL loss is the accumulation of hypoxia-inducible factor and hypoxia-related genes, such as VEGFA, which promote angiogenesis and stimulate tumor growth [5]. Moreover, VEGFA and its receptors are important therapeutic targets for ccRCC [6]. MicroRNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression at posttranscriptional level by binding to the 3′ untranslated region (3′UTR) of target messenger RNAs (mRNAs) [7].
Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma
2015, Neoplasia (United States)Citation Excerpt :VEGF is highly upregulated in RCC cells, likely because of mutations in the Von Hippel-Lindau gene, which induces degradation of hypoxia-inducible factor-1α through ubiquitination and is mutated in 75% of sporadic clear cell type RCCs [3]. VEGF is the key element in the pathogenesis of RCC, and VEGF receptor tyrosine kinase inhibitors have been successfully applied to treat RCC and have shown clinical benefits [4]. One multityrosine kinase inhibitor (TKI) that targets the VEGF and platelet derived growth factor (PDGF) receptor tyrosine kinases, sunitinib, has improved the outcomes of RCC patients compared with other therapies, such as cytokine therapy, and is currently considered a first-line option in patients with advanced RCC [5].
Signalling pathways involved in antitumoral effects of VIP in human renal cell carcinoma A498 cells: VIP induction of p53 expression
2014, International Journal of Biochemistry and Cell BiologyCitation Excerpt :This factor is, to date, the key element in the pathogenesis of RCC. VEGF pathway activation is responsible for the recruitment, migration, and expansion of endothelial cells, i.e. an angiogenesis tumour model characteristic of RCC (Albiges et al., 2011). The genetic alterations responsible for oncogenesis and tumour progression may underline the ability of renal cell carcinomas to switch to an angiogenic phenotype.
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These two authors are co–first authors and have contributed equally to the work.