Allosteric inhibition of HIF-2α as a novel therapy for clear cell renal cell carcinoma

Yu, Yancheng; Yu, Quanwei; Zhang, Xiaojin

doi:10.1016/j.drudis.2019.09.008

Cited by 46 publications

(18 citation statements)

References 53 publications

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“…VHL is a tumor suppressor gene and plays a key role in cellular oxygen sensing and the tumorigenesis of ccRCC. Previous studies demonstrated that inactivation of VHL was not significantly associated with anti-VEGF receptor (anti-VEGFR) inhibitors ( 17 , 18 ); however, it might predict the efficacy of HIF-2 inhibitors ( 19 ). In our study, PD-L1-positive expression was associated with a lower VHL mutation frequency, which indicates that most VHL -mutated ccRCC patients might not receive benefit from anti-PD-1/L1 inhibitors combined with anti-VEGFR inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Genomic Landscape in Chinese Clear Cell Renal Cell Carcinoma Patients

et al. 2021

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC). The genomic landscape in Chinese ccRCC needs to be elucidated. Herein, we investigated the molecular features of Chinese ccRCC patients. Genomic profiling of DNA was performed through next-generation sequencing (NGS) in Chinese patients with ccRCC between January 2017 and March 2020. Clinical information including age, gender, and tumor histology was collected. Immunohistochemistry (IHC) staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay or Ventana PD-L1 SP263 assay. Data analyses were performed using R 3.6.1. A total of 880 Chinese ccRCC patients who have undergone NGS were included in this study. The most common somatic alterations were detected in VHL (59.7%), PBRM1 (18.0%), SETD2 (12.2%), BAP1 (10.2%), and TP53 (9.4%). Compared with The Cancer Genome Atlas (TCGA) database, a higher mutation frequency of VHL (59.7% vs. 50.0%, p < 0.001) and TP53 (9.4% vs. 3.5%, p < 0.001) and a lower mutation frequency of PBRM1 (18.0% vs. 31.0%, p < 0.001) were found in the Chinese cohort. Of the 460 patients who were evaluated for PD-L1 expression, 139 (30.2%) had positive PD-L1 expression. The median tumor mutational burden (TMB) value was 4.5 muts/Mb (range, 0–46.0). Five (0.7%) patients were identified as microsatellite instability-high (MSI-H). Furthermore, 52 (5.9%) patients were identified to carry pathogenic or likely pathogenic germline mutations in 22 cancer predisposition genes. This is the first large-scale comprehensive genomic analysis for Chinese ccRCC patients, and these results might provide a better understanding of molecular features in Chinese ccRCC patients, which can lead to an improvement in the personalized treatment for these patients.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Genomic Landscape in Chinese Clear Cell Renal Cell Carcinoma Patients

et al. 2021

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“…Although the β-subunit of HIF is constitutively expressed, HIF-α protein is only expressed under hypoxic conditions and when VHL is inactivated ( 31 ). VHL promotes the degradation of HIF-α under normoxic conditions to keep the HIF-α subunit level low ( 32 ). Under hypoxic conditions, VHL is inactivated, leading to the accumulation of HIF-α, which binds to HIF-β and forms heterodimers that activate target genes.…”

Section: Important Inflammation-related Pathways In the Development Omentioning

confidence: 99%

Impact of inflammation and immunotherapy in renal cell carcinoma (Review)

et al. 2020

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Substantial research attention has been directed at exploring the mechanisms and treatment of renal cell carcinoma (RCC). Indeed, the association between inflammation and tumor phenotypes has been at the center of cancer research. Concomitant with research on the inflammation response and inflammatory molecules involved in RCC, new breakthroughs have emerged. A large body of knowledge now shows that treatments targeting inflammation and immunity in RCC provide substantial clinical benefits. Adequate analysis and a better understanding of the mechanisms of inflammatory factors in the occurrence and progression of RCC are highly desirable. Currently, numerous RCC treatments targeted at inflammation and immunotherapy are available. The current review describes in detail the link between inflammation and RCC.

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“…Overexpression of HIF2α is primarily expressed in high tumor-burden RCC, and HIF2α, but not HIF1α, induces cell death by reducing HIF-mediated transcription in VHL-defective RCC cells [112]. As such, HIF2α is predicted to exert oncogenic effects targeting genes such as VEGFA, FIK1, ANGPT1/Tie2, PDGFb, c-Myc, CXCR4 and MMP9l, which are related to angiogenesis, the cell cycle, and cell proliferation and metastasis [113][114][115][116][117][118]. Therefore, a more nuanced understanding of HIFα molecules has led to the development of HIF2α inhibitors.…”

Section: Return To Hifamentioning

confidence: 99%

Loss of Von Hippel–Lindau (VHL) Tumor Suppressor Gene Function: VHL–HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC)

Kim

Shim

Lee

et al. 2021

IJMS

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Renal cell carcinoma (RCC) is a malignancy of the kidney originating from the tubular epithelium. Inactivation of the von Hippel–Lindau tumor-suppressor gene (VHL) is found in most clear cell renal cell carcinomas (ccRCCs). The VHL–HIF–VEGF/VEGFR pathway, which involves the von Hippel–Lindau tumor suppressor protein (VHL), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and its receptor (VEGFR), is a well-studied therapeutic target for metastatic ccRCC. Therefore, over the past decade, anti-angiogenic agents targeting VEGFR have served as the standard treatment for metastatic RCC. Recently, based on the immunomodulatory effect of anti-VEGFR therapy, anti-angiogenic agents and immune checkpoint inhibitor combination strategies have also emerged as therapeutic strategies. These advances were made possible by the improved understanding of the VHL–HIF pathway. In this review, we summarize the historical evolution of ccRCC treatments, with a focus on the involvement of the VHL–HIF pathway.

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Allosteric inhibition of HIF-2α as a novel therapy for clear cell renal cell carcinoma

Cited by 46 publications

References 53 publications

Comprehensive Genomic Landscape in Chinese Clear Cell Renal Cell Carcinoma Patients

Comprehensive Genomic Landscape in Chinese Clear Cell Renal Cell Carcinoma Patients

Impact of inflammation and immunotherapy in renal cell carcinoma (Review)

Loss of Von Hippel–Lindau (VHL) Tumor Suppressor Gene Function: VHL–HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC)

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