New approaches to first-line treatment of advanced renal cell carcinoma

George, Daniel J.; Lee, Chung-Han; Heng, Daniel Yick Chin

doi:10.1177/17588359211034708

Cited by 28 publications

(22 citation statements)

References 83 publications

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“…5 A). Currently, TKIs are the first-line targeted treatment for ccRCC 26 . The acquired resistance to TKIs in ccRCC has become the major obstacle for improving the survival of ccRCC patients 27 .…”

Section: Resultsmentioning

confidence: 99%

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

Li¹,

Yan²,

Yu³

et al. 2022

Int. J. Biol. Sci.

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and has the highest mortality rate. For metastatic RCC, systemic drug therapy is the most important method in addition to surgical tumor reduction. In recent years, tyrosine kinase inhibitors (TKIs) targeting the angiogenesis have been applied to treat ccRCC and achieved profound therapeutic effects. It has been reported that most patients receiving antiangiogenic therapy will develop resistance within 15 months. The mechanism of resistance to targeted therapy is extremely complex and has not been clarified. Ovarian tumor-associated protease domain-containing proteins (OTUDs) belonging to DUBs play a critical role in the tumorigenesis of solid tumors. However, the specific role of OTUDs in ccRCC is still elusive. Here, we investigated the clinicopathological role of OTUD family members in ccRCC. We demonstrated that OTUD1 was downregulated in renal cancer and involved in the poor prognosis of renal cancer. Then, we showed that OTUD1 inhibits cancer cell growth. Moreover, analysis of OTUD1 RNA-seq data indicated that OTUD1 inhibition triggers the AKT and NF-kappa B pathways in renal cancer cells. Furthermore, OTUD1 interacts with PTEN and regulates its stability. Subsequently, we revealed that downregulation of OTUD1 contributes to the sensitivity of renal cancer cells to TKIs, and this effect was blocked by TNF/NF-kappa B inhibitors and AKT inhibitors. Thus, we identified that the OTUD1-PTEN axis suppresses tumor growth and regulates the resistance of renal cancer to TKIs.

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Section: Resultsmentioning

confidence: 99%

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

Li¹,

Yan²,

Yu³

et al. 2022

Int. J. Biol. Sci.

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“…Until 2017, the multikinase inhibitors sunitinib and pazopanib that primarily target VEGFR formed the frontline treatment for ccRCC ( Powles et al, 2021 ). The median progress free survival (PFS), OS and ORR for sunitinib and pazopanib are 8.4 and 9.5 months, 28.4 months and 29.3 months, and 25 and 31%, respectively ( George et al, 2021 ). The complexity of the VEGFR family may possibly be responsible for the inconsistent results.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Methylation-Regulating Genes Prognostic Signature to Predict the Prognosis and Aid Immunotherapy of Clear Cell Renal Cell Carcinoma

Zhang

Hong

et al. 2022

Front. Cell Dev. Biol.

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Methylation is one of the most extensive modifications of biological macromolecules and affects cell-fate determination, development, aging, and cancer. Several methylation modifications, including 5-methylcytosine and N6-methyladenosine, play an essential role in many cancers. However, little is known about the relationship between methylation and the prognosis of clear cell renal cell carcinoma (ccRCC). Here, we established a methylation-regulating genes prognostic signature (MRGPS) to predict the prognoses of ccRCC patients. We obtained ccRCC samples from The Cancer Genome Atlas and identified methylation-regulatingd genes (MRGs) from the Gene Set Enrichment Analysis database. We also determined differentially expressed genes (DEGs) and performed cluster analysis to identify candidate genes. Subsequently, we established and validated an MRGPS to predict the overall survival of ccRCC patients. This was also verified in 15 ccRCC samples collected from the Fujian Provincial Hospital via quantitative real-time transcription (qRT-PCR). While 95 MRGs were differentially expressed (DEGs1) between tumor and normal tissues, 17 MRGs were differentially expressed (DEGs2) between cluster 1 and 2. Notably, 13 genes common among DEGs1 and DEGs2 were identified as hub genes. In fact, we established three genes (NOP2, NSUN6, and TET2) to be an MRGPS based on their multivariate Cox regression analysis coefficients (p < 0.05). A receiver operating characteristic curve analysis confirmed this MRGPS to have a good prognostic performance. Moreover, the MRGPS was associated with characteristics of the tumor immune microenvironment and responses to inhibitor checkpoint inhibitors. Data from “IMvigor 210” demonstrated that patients with a low MRGPS would benefit more from atelozumab (p < 0.05). Furthermore, a multivariate analysis revealed that MRGPS was an independent risk factor associated with ccRCC prognosis (p < 0.05). Notably, a nomogram constructed by combining with clinical characteristics (age, grade, stage, and MRGPS risk score) to predict the overall survival of a ccRCC patient had a favorable predictive value. Eventually, our qRT-PCR results showed that tumor tissues had higher NOP2 and NSUN6 expression levels and lower TET2 expression than normal tissues of ccRCC samples. While the proposed MRGPS comprising NOP2, NSUN6, and TET2 can be an alternative prognostic biomarker for ccRCC patients, it is a promising index for personalized ICI treatments against ccRCC.

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“…RCC is a highly angiogenic and immunogenic tumor, and new evidence suggests a potential beneficial synergistic effect of combined treatment modalities encompassing TKIs and ICIs (PD-1 and CTLA-4). The latter is based on improved progression-free survival or/and overall survival outcomes [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

A Rare Presentation of Metastatic Renal Cell Carcinoma Masquerading as Vitritis: A Case Report and Review of Literature

2022

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We report a case of a 74-year-old gentleman who presented with floaters and decreased vision in the right eye after cataract surgery. His past medical history was significant for metastatic renal cell carcinoma (mRCC) to bone, lung and abdomen which was presumed stable for the last two years while on the tyrosine kinase inhibitor (TKI), pazopanib. Clinical examination revealed significant vitritis with a distinctive clumping of cells on the pre-retinal surface and posterior hyaloid face. Magnetic resonance imaging of the brain revealed new lesions suspicious for metastases. A diagnostic vitrectomy was performed to determine the nature of the vitritis and clear the visual axis. Cytopathologic evaluation of the vitreous demonstrated clusters of malignant cells that were positive for AE1/AE3 and PAX-8, and negative for the CD20, CD3, RCC, SOX-10 and S-100 immunohistochemical markers. The overall findings favored a metastatic RCC to the vitreous. Choroidal and retinal metastases from mRCC have been previously reported; however, vitreous involvement by mRCC with no evidence of retinal or choroidal mass has not been described. New treatments of mRCC include TKIs which target vascular endothelial growth factor receptors (VEGFRs). Herein, we analyze the factors that could have precipitated this unusual metastasis to the vitreous.

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New approaches to first-line treatment of advanced renal cell carcinoma

Cited by 28 publications

References 83 publications

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

OTUD1 stabilizes PTEN to inhibit the PI3K/AKT and TNF-alpha/NF-kappaB signaling pathways and sensitize ccRCC to TKIs

Identification of a Methylation-Regulating Genes Prognostic Signature to Predict the Prognosis and Aid Immunotherapy of Clear Cell Renal Cell Carcinoma

A Rare Presentation of Metastatic Renal Cell Carcinoma Masquerading as Vitritis: A Case Report and Review of Literature

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