Adjuvant Therapy for Renal Cell Carcinoma

Pinto, Álvaro

doi:10.1016/j.clgc.2014.06.012

Cited by 5 publications

(7 citation statements)

References 37 publications

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“…These results suggests that the determination of protein levels of uPA system components in patients with pT1 and pT2 tumours may provide additional prognostic information that may allow for individual, risk-adapted therapy decisions. Patients at higher risk of relapse could be treated by targeted agents in an adjuvant setting as currently evaluated in a number of ongoing prospective clinical trials [6]. For primary breast cancer, the determination of uPA and PAI-1 antigen levels in tumour tissue extracts has already entered clinical practice for risk stratification and individual therapy decisions in patients with lymph node-negative disease [16, 38].…”

Section: Discussionmentioning

confidence: 99%

“…A reliable prediction of outcome after nephrectomy by such markers would be valuable to tailor individualised follow-up schedules and to provide adjuvant therapies to patients at high risk of relapse [6]. Several clinicopathological parameters and molecular biomarkers or their combination have been described to be prognostically useful for RCC [7–9].…”

Section: Introductionmentioning

confidence: 99%

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Prognostic impact of urokinase-type plasminogen activator system components in clear cell renal cell carcinoma patients without distant metastasis

Fuessel

Erdmann

Täubert³

et al. 2014

BMC Cancer

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BackgroundMembers of the urokinase-type plasminogen activator (uPA) system including uPA, its receptor uPAR and the plasminogen activator inhibitor 1 (PAI-1) play an important role in tumour invasion and progression in a variety of tumour types. Since the majority of clear cell renal cell carcinoma (ccRCC) shows distant metastasis at time of diagnosis or later, the interplay of uPA, uPAR and PAI-1 might be of importance in this process determining the patients’ outcome.MethodsCorresponding pairs of malignant and non-malignant renal tissue specimens were obtained from 112 ccRCC patients without distant metastasis who underwent tumour nephrectomy. Tissue extracts prepared from fresh-frozen tissue samples by detergent extraction were used for the determination of antigen levels of uPA, uPAR and PAI-1 by ELISA. Antigen levels were normalised to protein concentrations and expressed as ng per mg of total protein.ResultsAntigen levels of uPA, uPAR, and PAI-1 correlated with each other in the malignant tissue specimens (rs=0.51-0.65; all P<0.001). Antigen levels of uPA system components were significantly higher in tissue extracts of non-organ confined tumours (pT3+4) compared to organ-confined tumours (pT1+2; all P<0.05). Significantly elevated levels of uPAR and PAI-1 were also observed in high grade ccRCC. When using median antigen levels as cut-off points, all three uPA system factors were significant predictors for disease-specific survival (DSS) in univariate Cox’s regression analyses. High levels of uPA and uPAR remained independent predictors for DSS with HR=2.86 (95% CI 1.07-7.67, P=0.037) and HR=4.70 (95% CI 1.51-14.6, P=0.008), respectively, in multivariate Cox’s regression analyses. A combination of high antigen levels of uPA and/or uPAR further improved the prediction of DSS in multivariate analysis (HR=14.5, 95% CI 1.88-111.1, P=0.010). Moreover, high uPA and/or uPAR levels defined a patient subgroup of high risk for tumour-related death in ccRCC patients with organ-confined disease (pT1+2) (HR=9.83, 95% CI 1.21-79.6, P=0.032).ConclusionsHigh levels of uPA and uPAR in tumour tissue extracts are associated with a significantly shorter DSS of ccRCC patients without distant metastases.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-974) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prognostic impact of urokinase-type plasminogen activator system components in clear cell renal cell carcinoma patients without distant metastasis

Fuessel

Erdmann

Täubert³

et al. 2014

BMC Cancer

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“…Another class of CC-RCC therapeutics is represented by mammalian target of rapamycin inhibitors (mTORi) everolimus 13 and temsirolimus 14 , which prolong progression-free survival for a median of 3 months when used as single agents compared to standard of care. While these treatments offer significant clinical benefit, resistance to both RTKi and mTORi therapeutics develops quickly creating the need for new and improved therapeutics 15 – 17 .…”

Section: Introductionmentioning

confidence: 99%

Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma

et al. 2016

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Clear Cell Renal Cell Carcinoma (CC-RCC) is the most lethal of all genitourinary cancers. The functional loss of the von Hippel-Lindau (VHL) gene occurs in 90% of CC-RCC, driving cancer progression. The objective of this study was to identify chemical compounds that are synthetically lethal with VHL deficiency in CC-RCC. An annotated chemical library, the Library of Pharmacologically Active Compounds (LOPAC), was screened in parallel on VHL-deficient RCC4 cells and RCC4VHL cells with re-introduced VHL cDNA. The ROCK inhibitor, Y-27632, was identified and validated for selective targeting of VHL-deficient CC-RCC in multiple genetic backgrounds by clonogenic assays. Downregulation of ROCK1 by siRNA selectively reduced the colony forming ability of VHL-deficient CC-RCC, thus mimicking the effect of Y-27632 treatment, whereas downregulation of ROCK2 had no effect. In addition, two other ROCK inhibitors, RKI 1447 and GSK 429286, selectively targeted VHL-deficient CC-RCC. CC-RCC treatment with ROCK inhibitors is cytotoxic and cytostatic based on BrdU assay, Propidium Iodide (PI) staining, and growth curves; and blocks cell migration based on transwell assay. Importantly, knockdown of Hypoxia Inducible Factor (HIF) β in the VHL-deficient CC-RCC had a protective effect against Y-27632 treatment, mimicking VHL reintroduction. On the other hand, CC-RCCVHL cells were sensitized to Y-27632 treatment in hypoxia (2% O2). These results suggest that synthetic lethality between ROCK inhibition and VHL deficiency is dependent on HIF activation. Moreover, HIF1α or HIF2α overexpression in CC-RCCVHL cells is sufficient to sensitize them to ROCK inhibition. Finally, Y-27632 treatment inhibited growth of subcutaneous 786-OT1 CC-RCC tumors in mice. Thus, ROCK inhibitors represent potential therapeutics for VHL-deficient CC-RCC.

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“…3 Despite a large, intensive clinical study program adjuvant treatment after nephrectomy still does not have an established role in RCC. 4 Considering the often limiting side effects and high cost of adjuvant treatment modalities, determining prognostic factors to more accurately select patients at high risk for disease recurrence is strongly warranted. 1,4,5 To improve PA for RCC and categorize patients into risk groups several prognostic models have been developed, namely risk scores and nomograms.…”

mentioning

confidence: 99%

“…4 Considering the often limiting side effects and high cost of adjuvant treatment modalities, determining prognostic factors to more accurately select patients at high risk for disease recurrence is strongly warranted. 1,4,5 To improve PA for RCC and categorize patients into risk groups several prognostic models have been developed, namely risk scores and nomograms. The prognostic usefulness of most of them has been confirmed in external validation cohorts.…”

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confidence: 99%

The Preoperative AST/ALT (De Ritis) Ratio Represents a Poor Prognostic Factor in a Cohort of Patients with Nonmetastatic Renal Cell Carcinoma

et al. 2015

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Adjuvant Therapy for Renal Cell Carcinoma

Cited by 5 publications

References 37 publications

Prognostic impact of urokinase-type plasminogen activator system components in clear cell renal cell carcinoma patients without distant metastasis

Prognostic impact of urokinase-type plasminogen activator system components in clear cell renal cell carcinoma patients without distant metastasis

Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma

The Preoperative AST/ALT (De Ritis) Ratio Represents a Poor Prognostic Factor in a Cohort of Patients with Nonmetastatic Renal Cell Carcinoma

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