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Updated: May 31, 2025
Induction and Testing of Hypoxia in Cell Culture
Published on: August 12, 2011
Hypoxia-Inducible Factor in Renal Cell Carcinoma: From Molecular Insights to Targeted Therapies
Giandomenico Roviello1, Irene De Gennaro2, Ismaela Vascotto2
1Department of Health Science, University of Florence, 50134 Florence, Italy.
Abstract:
Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene occur frequently in clear cell renal cell carcinoma (RCC), the predominant histology of kidney cancer, and have been associated with its pathogenesis and progression. Alterations of VHL lead to impaired degradation of hypoxia-inducible factor 1α (HIF1α) and HIF2α promoting neoangiogenesis, which is pivotal for cancer growth. As such, targeting the VHL-HIF axis holds relevant potential for therapeutic purposes. Belzutifan, an HIF-2α inhibitor, has been recently indicated for metastatic RCC and other antiangiogenic drugs directed against HIF-2α are currently under investigation. Further, clinical and preclinical studies of combination approaches for metastatic RCC including belzutifan with cyclin-dependent kinase 4-6 inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors achieved promising results or are ongoing. This review aims to summarize the existing evidence regarding the VHL/HIF pathway, and the approved and emerging treatment strategies that target this pivotal molecular axis and their mechanisms of resistance.
Insights
Mutations in the VHL gene drive clear cell renal cell carcinoma by stabilizing HIF. Targeting the VHL-HIF pathway with drugs like belzutifan offers new therapeutic strategies for kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Clear cell renal cell carcinoma (RCC) frequently involves von Hippel-Lindau (VHL) tumor suppressor gene mutations.
- VHL alterations disrupt hypoxia-inducible factor (HIF) degradation, promoting tumor angiogenesis and growth.
Purpose of the Study:
- To review the VHL/HIF pathway's role in clear cell RCC pathogenesis.
- To summarize current and emerging therapeutic strategies targeting the VHL-HIF axis.
- To discuss mechanisms of resistance to these therapies.
Main Methods:
- Literature review of preclinical and clinical studies.
- Analysis of VHL/HIF pathway alterations in RCC.
- Evaluation of targeted therapies and combination approaches.
Main Results:
- VHL-HIF pathway dysregulation is central to clear cell RCC.
- Belzutifan, an HIF-2α inhibitor, is approved for metastatic RCC.
- Combination therapies (e.g., belzutifan with CDK4/6 inhibitors, TKIs, ICIs) show promise.
Conclusions:
- Targeting the VHL-HIF axis is a validated therapeutic strategy for clear cell RCC.
- Emerging combination treatments offer new hope for patients with metastatic disease.
- Understanding resistance mechanisms is crucial for optimizing VHL-HIF-targeted therapies.
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