Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, 08035 Barcelona, Spain.
Med Sci (Basel). 2023 Jun 30;11(3):46. doi: 10.3390/medsci11030046.
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.
von Hippel-Lindau (VHL) 缺失是特征性的肾透明细胞癌亚型（ccRCC）的标志性事件。生殖细胞 VHL 突变携带者的肾囊肿和 ccRCC 以及血管母细胞瘤、嗜铬细胞瘤和胰腺神经内分泌肿瘤的患病率增加。在散发性和遗传性 ccRCC 中，VHL 介导的致癌作用的主要机制是缺氧诱导因子（HIF1A 和 HIF2A）的异常稳定。虽然 HIF1A 作为肿瘤抑制因子，经常通过失活突变/14q 染色体缺失而丢失，但 HIF2A 作为致癌基因，促进其靶基因（VEGF、PDGF、CAIX Oct4 等）的表达。选择性 HIF2a 抑制剂阻止 HIF2a 与 ARNT 的异二聚化，阻止 HIF2a 诱导的转录。几种 HIF2a 抑制剂已进入临床试验，它们表现出有利的毒性特征，表现为贫血、疲劳和水肿，并在经过大量预处理的 ccRCC 患者中显示出有希望的活性。Belzutifan，第二代 HIF2a 抑制剂，是第一个获得 FDA 批准用于治疗 VHL 综合征中不可切除的 ccRCC 的药物。在这篇综述中，我们总结了 HIF2a 阻断在 ccRCC 中的作用机制，总结了从临床前模型到引入临床的 HIF2a 抑制剂的开发情况，重点介绍了 Belzutifan，并讨论了它们在 VHL 疾病管理中的作用。
