Hypoxia-Inducible Factor in Renal Cell Carcinoma: From Molecular Insights to Targeted Therapies

Giandomenico Roviello; Irene De Gennaro; Ismaela Vascotto; Giulia Venturi; Alberto D’Angelo; Costanza Winchler; Adriana Guarino; Salvatore Cacioppo; Mikol Modesti; Marinella Micol Mela; Edoardo Francini; Laura Doni; Virginia Rossi; Elisabetta Gambale; Roberta Giorgione; Lorenzo Antonuzzo; Gabriella Nesi; Martina Catalano

doi:10.3390/genes16010006

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Hypoxia-Inducible Factor in Renal Cell Carcinoma: From Molecular Insights to Targeted Therapies

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Hypoxia-Inducible Factor in Renal Cell Carcinoma: From Molecular Insights to Targeted Therapies

Giandomenico Roviello, Irene De Gennaro, Ismaela Vascotto, Giulia Venturi, Alberto D’Angelo, Costanza Winchler, Adriana Guarino, Salvatore Cacioppo, Mikol Modesti, Marinella Micol Mela, …

Genes, Vol.16(1), 6

01/01/2025

DOI: 10.3390/genes16010006

PMID: 39858553

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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.

belzutifan

HIF-2α targeting

renal cell carcinoma

VHL tumor

Details

Title: Subtitle: Hypoxia-Inducible Factor in Renal Cell Carcinoma: From Molecular Insights to Targeted Therapies
Creators: Giandomenico Roviello - University of Florence
Irene De Gennaro - University of Florence
Ismaela Vascotto - University of Florence
Giulia Venturi - University of Florence
Alberto D’Angelo - Sheffield Teaching Hospitals NHS Foundation Trust
Costanza Winchler - University of Florence
Adriana Guarino - University of Florence
Salvatore Cacioppo - University of Florence
Mikol Modesti - University of Florence
Marinella Micol Mela - Azienda Ospedaliero-Universitaria Careggi
Edoardo Francini - University of Florence
Laura Doni - Azienda Ospedaliero-Universitaria Careggi
Virginia Rossi - Azienda Ospedaliero-Universitaria Careggi
Elisabetta Gambale - Azienda Ospedaliero-Universitaria Careggi
Roberta Giorgione - University of Florence
Lorenzo Antonuzzo - University of Florence
Gabriella Nesi - University of Florence
Martina Catalano - University of Florence
Resource Type: Journal article
Publication Details: Genes, Vol.16(1), 6
DOI: 10.3390/genes16010006
PMID: 39858553
ISSN: 2073-4425
eISSN: 2073-4425
Language: English
Date published: 01/01/2025
Academic Unit: Internal Medicine
Record Identifier: 9985221145802771

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