Cuvillier Olivier
CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse, France ; Université de Toulouse, UPS, Toulouse, France.
Transl Androl Urol. 2017 Feb;6(1):131-133. doi: 10.21037/tau.2017.01.12.
Hypoxia, the insufficient delivery of oxygen for the demand of a tissue, contributes to the development of an aggressive phenotype, resistance to radiation therapy and chemotherapy, and is predictive of a poor outcome in numerous tumor types. Adaptation to hypoxia is mediated by hypoxia-inducible factors (HIFs), including HIF-1α and HIF-2α, which regulate genes promoting angiogenesis, increased tumor growth or metastasis. In kidney cancer, HIF-2α is believed to be the most important driver for development and progression of clear cell renal cell carcinoma (ccRCC), highlighting the therapeutic potential of HIF-2 antagonists in this disease. Recent studies show that HIF-2α can be targeted by selective, and orally active new class of inhibitors. In conjunction with the restricted expression of HIF-2α in normal adult physiology, these studies suggest that such therapeutic approach might be favorable for patients with lower toxicity than current anti-angiogenic drugs like sunitinib. However, the differential sensitivity to these HIF-2α antagonists along with the potential mechanisms of resistance reported in these studies advocate for the identification of biomarkers to determine which patients are more likely to benefit from these therapies as well as paving the way for second generation inhibitors or complementary inhibitory approaches.
缺氧，即组织供氧不足以满足其需求，会促使侵袭性表型的发展、导致对放射治疗和化疗产生抗性，并且在多种肿瘤类型中预示着不良预后。对缺氧的适应由缺氧诱导因子（HIFs）介导，包括HIF-1α和HIF-2α，它们调控促进血管生成、增加肿瘤生长或转移的基因。在肾癌中，HIF-2α被认为是透明细胞肾细胞癌（ccRCC）发生和进展的最重要驱动因素，这凸显了HIF-2拮抗剂在该疾病中的治疗潜力。最近的研究表明，HIF-2α可被一类新型的选择性口服活性抑制剂靶向作用。鉴于HIF-2α在正常成人生理中的表达受限，这些研究表明，这种治疗方法可能对患者有利，其毒性低于目前的抗血管生成药物如舒尼替尼。然而，这些研究中报道的对这些HIF-2α拮抗剂的不同敏感性以及潜在的耐药机制，主张识别生物标志物，以确定哪些患者更可能从这些治疗中获益，并为第二代抑制剂或补充性抑制方法铺平道路。
