Germline inactivation of the Von Hippel-Lindau (VHL) tumor suppressor is the defining hallmark in hereditary VHL disease and VHL-associated renal cell carcinoma (RCC). However, somaticVHLmutations are also observed in patients with sporadic RCC. Loss of functionVHLmutations result in constitutive activation of hypoxia-inducible factor-2 alpha (HIF-2α), which leads to increased expression of HIF target genes that promote angiogenesis and tumor growth. As of 2023, belzutifan is currently the only approved HIF-2α inhibitor for both VHL-associated and sporadic metastatic RCC (mRCC). However, there is potential for resistance with HIF-2α inhibitors which warrants novel HIF-2α-targeting strategies. In this review, we discuss the potential resistance mechanisms with belzutifan and current clinical trials evaluating novel combinations of belzutifan with other targeted therapies and immune checkpoint inhibitors which may enhance the efficacy of HIF-2α targeting. Lastly, we also discuss newer generation HIF-2α inhibitors that are currently under early investigation and outline future directions and challenges with HIF-2α inhibitors for mRCC.
Von Hippel-Lindau（VHL）肿瘤抑制基因的种系失活是遗传性VHL病及VHL相关肾细胞癌（RCC）的标志性特征。然而，在散发性RCC患者中也观察到体细胞VHL突变。VHL功能缺失性突变导致缺氧诱导因子-2α（HIF-2α）的持续激活，进而促进血管生成和肿瘤生长的HIF靶基因表达上调。截至2023年，贝组替凡是目前唯一获批用于VHL相关性和散发性转移性RCC（mRCC）的HIF-2α抑制剂。然而，HIF-2α抑制剂存在潜在的耐药风险，这促使我们需要开发新型HIF-2α靶向策略。本综述探讨了贝组替凡的潜在耐药机制，并评述了当前评估贝组替凡与其他靶向疗法及免疫检查点抑制剂联合应用的临床试验，这些联合策略可能增强HIF-2α靶向治疗的疗效。最后，我们还讨论了目前处于早期研究阶段的新一代HIF-2α抑制剂，并展望了HIF-2α抑制剂治疗mRCC的未来发展方向与挑战。
Novel Approaches with HIF-2α Targeted Therapies in Metastatic Renal Cell Carcinoma
肿瘤(癌症)患者之家