A Study of Angiogenesis Markers in Patients with Renal Cell Carcinoma Undergoing Therapy with Sunitinib

Stubbs, Clive; Bardoli, Antonio D; Afshar, Mehran; Pirrie, Sarah; Miscoria, Manuela; Wheeley, Isabella; Porfiri, Emilio

doi:10.21873/anticanres.11315

Cited by 14 publications

(10 citation statements)

References 16 publications

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“…In mRCC, several serum, urinary and plasma biomarkers have recently been described, 36 including elevated circulating MMPs, 37,38 as well as neovascularity. 39 However, our study demonstrates for the first time the presence of sVE in the serum from RCC patients, as well as a SUT-cycle-dependent decrease of sVE level for patients who responded to the therapy.…”

Section: Discussionmentioning

confidence: 99%

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma

et al. 2018

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Section: Discussionmentioning

confidence: 99%

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma

et al. 2018

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“…A previous investigation demonstrated that RCC patients with VEGF-A-2578 genotype had poor prognosis, including a higher death risk, a larger tumor size, and a worse tumor grade, compared with patients carrying other genotypes [ 47 ]. In a study exploring the correlation between angiogenetic markers and RCC outcomes, VEGF-A was found positive in more tumors of immunohistochemistry results [ 48 ]. The VEGF-A gene contains eight exons, which are not present in the one VEGF-A at the same time [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

USP39 promotes malignant proliferation and angiogenesis of renal cell carcinoma by inhibiting VEGF-A165b alternative splicing via regulating SRSF1 and SRPK1

Pan

Chen

et al. 2021

Cancer Cell Int

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Background The benefit of targeted therapy for renal cell carcinoma (RCC) is largely crippled by drug resistance. Rapid disease progression and poor prognosis occur in patients with drug resistance. New treatments demand prompt exploration for clinical therapies. Ubiquitin-specific peptidase 39 (USP39) serves as the pro-tumor factor in several previous studies of other malignant tumors. To investigate the function and mechanism of USP39 in promoting malignant proliferation and angiogenesis of RCC. Methods We applied ONCOMINE database to analyze the correlation between USP39 expression level and the clinical characteristics of RCC. USP39 knockdown or overexpression plasmids were transfected into 786-O and ACHN cells. The HUVEC received cell supernatants of 786-O and ACHN cells with knockdown or overexpression USP39.The effect of USP39 on RCC was evaluated by MTT assay, cell cycle analysis, colony formation assay and tubule formation assay. The interaction between USP39 and VEGF-A alternative splicing was assessed by affinity purification and mass spectrometry, co-immunoprecipitation and Western blot assays. Results The mRNA expression level of USP39 in RCC was significantly higher than that in normal renal tissue (P < 0.001), and negatively correlated with the survival rate of RCC patients (P < 0.01). Silencing of USP39 in 786-O and ACHN cells inhibited cell proliferation and colony formation, and induced S phase arrest. USP39 overexpression significantly increased the number of tubules (P < 0.05) and branches (P < 0.01) formed by HUVEC cells, and USP39 knockdown produced an opposite effect (P < 0.05). The USP39 (101–565) fragment directly mediated its binding to SRSF1 and SRPK1, and promoted the phosphorylation of SRSF1 to regulate VEGF-A alternative splicing. USP39 knockdown upregulated the expression of VEGF-A165b, and USP39 overexpression downregulated the expression of VEGF-A165b significantly (both P < 0.05). Conclusion USP39 acted as a pro-tumor factor by motivating the malignant biological processes of RCC, probably through inhibiting VEGF-A165b alternative splicing and regulating SRSF1 and SRPK1. USP39 may prove to be a potential therapeutic target for RCC. Graphic abstract

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“…In fact, escape from VEGFR2 signaling dependency has been proposed as a mechanism of acquired resistance to the multi-targeted TKIs [ 17 ]. In a recent retrospective analysis of archived renal cell carcinoma patients treated with sunitinib, Stubbs and colleagues found no association between KDR expression and overall or progression-free survival, but did not assess mutations [ 18 ]. However, a retrospective study of 275 sarcoma patients identify a significant correlation between high VEGFR2 protein expression and decreased patient survival (p <0.001) [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor exome sequencing and copy number alterations reveal potential predictors of intrinsic resistance to multi-targeted tyrosine kinase inhibitors

et al. 2017

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Multi-targeted tyrosine kinase inhibitors (TKIs) have broad efficacy and similar FDA-approved indications, suggesting shared molecular drug targets across cancer types. Irrespective of tumor type, 20-30% of patients treated with multi-targeted TKIs demonstrate intrinsic resistance, with progressive disease as a best response. We conducted a retrospective cohort study to identify tumor (somatic) point mutations, insertion/deletions, and copy number alterations (CNA) associated with intrinsic resistance to multi-targeted TKIs. Using a candidate gene approach (n=243), tumor next-generation sequencing and CNA data was associated with resistant and non-resistant outcomes. Resistant individuals (n=11) more commonly harbored somatic point mutations in NTRK1, KDR, TGFBR2, and PTPN11 and CNA in CDK4, CDKN2B, and ERBB2 compared to non-resistant (n=26, p<0.01). Using a random forest classification model for variable reduction and a decision tree classification model, we were able to differentiate intrinsically resistant from non-resistant patients. CNA in CDK4 and CDKN2B were the most important analytical features, implicating the cyclin D pathway as a potentially important factor in resistance to multi-targeted TKIs. Replication of these results in a larger, independent patient cohort has potential to inform personalized prescribing of these widely utilized agents.

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A Study of Angiogenesis Markers in Patients with Renal Cell Carcinoma Undergoing Therapy with Sunitinib

Abstract: The OS and PFS achieved by our patients reflected previous observations seen with sunitinib, but no correlation was found between expression of angiogenesis markers and clinical outcome.

Cited by 14 publications

References 16 publications

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma

USP39 promotes malignant proliferation and angiogenesis of renal cell carcinoma by inhibiting VEGF-A165b alternative splicing via regulating SRSF1 and SRPK1

Tumor exome sequencing and copy number alterations reveal potential predictors of intrinsic resistance to multi-targeted tyrosine kinase inhibitors

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