Selective HIF2A Inhibitors in the Management of Clear Cell Renal Cancer and Von Hippel–Lindau-Disease-Associated Tumors

Abstract

Von Hippel–Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.

Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases

“…Hypoxia-inducible factor (HIF) is the most important regulator of erythropoietin release ( 35 ). Von Hippel-Lindau (VHL) disease predisposes to CCRCC by stabilization of HIF, thereby leading to increased and continuous stimulation of the EPO cell, both functionally and proliferatively ( 36 ). Lack of VHL factor function is also central in CCRCCs in general ( 37 , 38 ), but the cancers not being a part of inherent VHL disease manifest themselves a few decades later.…”

“…The prolonged hyperstimulation by HIF causing CCRCC resembles how excessive gastrin hyperstimulation leads to gastric cancer and is another example of cancer developing from a differentiated cell exposed to prolonged hyperstimulation. This improved understanding of the pathogenesis of CCRCC has already resulted in potentially improved treatments such as using HIF inhibitors ( 36 ).…”

Rationale for immune checkpoint inhibitors plus targeted therapy for advanced renal cell carcinoma

“…It was also the first HIF inhibitor to be approved for the treatment of VHL-associated RCC and other VHL-associated cancers based on satisfactory safety and efficacy. The latest results on Belzutifan and other novel HIF-2α inhibitors are currently awaiting further investigation in several phase 2 or 3 clinical trials [ 209 ].…”

Hypoxic Effects on Matrix Metalloproteinases’ Expression in the Tumor Microenvironment and Therapeutic Perspectives

“…Unlike HIF-1α, HIF-2α is only expressed in some cell types, such as the clear cell subtype of RCC (ccRCC), the most prevalent type of renal cancer [93]. In this regard, ccRCC cells have mutations in the VHL gene and, in 40% of the cases, in the HIF-1α gene with a HIF-2α overexpression due to decreased degradation.…”