Targeting the HIF2-VEGF axis in renal cell carcinoma
Targeting the HIF2-VEGF axis in renal cell carcinoma
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DOI：
10.1038/s41591-020-1093-z
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发表时间：
2020-10-05
期刊：
影响因子：
82.9
通讯作者：
Kaelin, William G., Jr.
中科院分区：
文献类型：
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作者：
Choueiri, Toni K.;Kaelin, William G., Jr.
靶向HIF氧敏感通路的抗癌疗法正在进入临床，特别是在肾癌中。对肿瘤抑制因子pVHL在氧敏感中的作用的认识促使了靶向转录因子HIF或HIF反应性生长因子（如VEGF）的药物的测试，用于治疗由VHL激活引起的癌症，如透明细胞肾细胞癌（ccRCC）。多种VEGF抑制剂现已被批准用于治疗ccRCC，并且HIF 2 α抑制剂已进入该疾病的3期开发。这些抑制剂现在也越来越多地与免疫检查点阻断剂结合使用。在这方面，我们描述了氧传感和缺氧信号传导机制的理解，导致了VHL相关肿瘤患者的HIF 2 α靶向治疗的发展。我们还提出了将这些疗法扩展到其他癌症的未来方向。
Anticancer therapies that target the HIF oxygen-sensing pathways are moving into the clinic, in particular in kidney cancer.Insights into the role of the tumor suppressor pVHL in oxygen sensing motivated the testing of drugs that target the transcription factor HIF or HIF-responsive growth factors, such as VEGF, for the treatment of cancers caused byVHLinactivation, such as clear-cell renal cell carcinoma (ccRCC). Multiple VEGF inhibitors are now approved for the treatment of ccRCC, and a HIF2 alpha inhibitor has advanced to phase 3 development for this disease. These inhibitors are now also increasingly combined with immune-checkpoint blockers. In this Perspective, we describe the understanding of the mechanisms of oxygen sensing and hypoxia signaling that resulted in the development of HIF2 alpha-targeted therapies for patients with VHL-associated tumors. We also present future directions for extending the use of these therapies to other cancers.