在肾透明细胞癌中 HIF 靶向治疗的演变。

Evolution of the HIF targeted therapy in clear cell renal cell carcinoma.

机构信息

The Minimally Invasive Urology Institute at The Miriam Hospital, Division of Urology, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States.

出版信息

Cancer Treat Rev. 2023 Dec;121:102645. doi: 10.1016/j.ctrv.2023.102645. Epub 2023 Oct 15.

DOI:10.1016/j.ctrv.2023.102645

PMID:37879247

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, affecting hundreds of thousands of people worldwide and can affect people of any age. The pathogenesis of ccRCC is most commonly due to biallelic loss of the tumor suppressor gene VHL. VHL is the recognition subunit of an E3-ubiquitin-ligase-complex essential for degradation of the hypoxia-inducible factors (HIF) 1α and 2α. Dysfunctional degradation of HIF results in overaccumulation, which is particularly concerning with the HIF2α subunit. This leads to nuclear translocation, dimerization, and transactivation of numerous HIF-regulated genes responsible for cell survival and proliferation in ccRCC. FDA-approved therapies for RCC have primarily focused on targeting downstream effectors of HIF, then incorporated immunotherapeutics, and now, novel approaches are moving back to HIF with a focus on interfering with upstream targets. This review summarizes the role of HIF in the pathogenesis of ccRCC, novel HIF2α-focused therapeutic approaches, and opportunities for ccRCC treatment.

摘要

透明细胞肾细胞癌（ccRCC）是最常见的肾癌类型，影响全球数十万人，可发生于任何年龄。ccRCC 的发病机制最常见于肿瘤抑制基因 VHL 的双等位基因缺失。VHL 是 E3-泛素连接酶复合物的识别亚基，该复合物对于缺氧诱导因子（HIF）1α和 2α的降解至关重要。HIF 的功能失调性降解导致其过度积累，这在 HIF2α亚基中尤其令人担忧。这导致核易位、二聚化和许多 HIF 调节基因的转录激活，这些基因在 ccRCC 中负责细胞存活和增殖。美国食品和药物管理局批准的 RCC 治疗方法主要集中在针对 HIF 的下游效应物，然后纳入免疫治疗药物，现在，新的方法又重新集中在 HIF 上，重点是干扰上游靶点。本综述总结了 HIF 在 ccRCC 发病机制中的作用、新型 HIF2α 靶向治疗方法以及 ccRCC 治疗的机会。