The level of FSHR expression in the primary kidney tumors to predict the response to subsequent antiangiogenic therapy with sunitinib.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21138-e21138
Author(s):  
Muhammad Ahsan Siraj ◽  
Christophe Pichon ◽  
Aurelian Radu ◽  
Nicolae Ghinea
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Sensitivity And Specificity ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Total Density ◽  
Kidney Tumors ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors

e21138 Background: Sunitinib is an antiangiogenic receptor tyrosine kinase inhibitor used to treat advanced metastatic renal cell carcinoma and other types of cancer. Sunitinib is effective in only approx. 70% of clear cell renal cell carcinoma (CCRCC) patients, has significant adverse side effects, and no method is available to predict which patients will not respond. Our purpose was to explore the possibility of introducing an effective prediction method based on a marker of the tumor vasculature, the Follicle Stimulating Hormone Receptor (FSHR). Methods: Using immunohistochemistry on paraffin sections with anti-FSHR monoclonal antibodies we studied by photonic and fluorescence microscopy the expression of FSHR in 50 patients diagnosed with advanced metastatic CCRCC. All patients were subjected to surgery for removal of the primary tumor and were subsequently treated with sunitinib orally for ≥ 3 months with a dose of 50 mg/day for 4 weeks followed by 2 weeks off. After therapy the patients were categorized as “responsive”, “stable”, or “non-responsive” based on the RECIST guidelines. The blood vessel density and the percentage of FSHR-positive vessels were determined by immunofluorescence on sections from the primary tumors removed by surgery, prior to the sunitinib treatment. Von Willebrand factor (vWF) was used as specific endothelial marker. Results: There were no significant differences in the total density of vessels (detected with anti-vWF antibody) among the responsive, stable and non-responsive patients. The percentage of FSHR-stained vessels was on average five fold higher for the patients that responded to the treatment in comparison with the stable group and almost eight fold higher than in the non-responsive group. The percentage allowed the detection of responders with 87-100% sensitivity and specificity. Conclusions: The data suggest that FSHR expression levels in the blood vessels of CCRCC primary tumors can be used to predict, with high sensitivity and specificity, the patients that will respond to sunitinib therapy.

scholarly journals MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Brian Shuch ◽  
Ryan Falbo ◽  
Fabio Parisi ◽  
Adebowale Adeniran ◽  
Yuval Kluger ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Predictive Biomarkers ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors ◽  
Distant Tissue ◽  
Significant Expression ◽  
Metastatic Sites

Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available.Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1). MET expression weakly correlated between primary and matched metastatic sites (R=0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39).Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.

scholarly journals Cabozantinib for the Management of Metastatic Clear Cell Renal Cell Carcinoma

2018 ◽  
Vol 5 (4) ◽  
pp. 1-5 ◽  
Author(s):  
Sharon Del Vecchio ◽  
Robert J Ellis
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Current Treatment ◽  
Phase Iii ◽  
Solid Organ ◽  
Cell Renal Cell Carcinoma ◽  
Randomised Controlled

Cabozantinib is a multi-tyrosine kinase inhibitor used for the treatment of various solid-organ tumours. It was recently approved as a first- and second-line therapeutic for the management of advanced/metastatic renal cell carcinoma based on the results of two randomised controlled trials. The phase III METEOR trial compared cabozantinib against everolimus as a second- or greater line therapy and found benefits in progression-free and overall survival, and the phase II CABOSUN trial compared cabozantinib against sunitinib as a first-line therapeutic and found benefits in terms of progression-free survival. This review briefly summarises how cabozantinib fits into current treatment paradigms for the management of advanced renal cell carcinoma.

scholarly journals Exceptional Response of Metastatic Chromophobe Renal Cell Carcinoma to Vascular Endothelial Growth Factor (VEGF) Inhibitors: Should Increased VEGF-C Expression Be Used to Guide Treatment?

2019 ◽  
Vol 2019 ◽  
pp. 1-6
Author(s):  
Jacob W. Bruinius ◽  
Karl J. Dykema ◽  
Sabrina L. Noyes ◽  
Bin Tean Teh ◽  
Brian R. Lane
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Clear Cell ◽  
Locally Advanced ◽  
Chromophobe Renal Cell Carcinoma ◽  
Molecular Profile ◽  
Vegf Inhibitors ◽  
Cell Renal Cell Carcinoma

There is sparse literature demonstrating effective treatments for metastatic chromophobe renal cell carcinoma (ChRCC). The tyrosine kinase inhibitor (TKI) sunitinib selectively inhibits the VEGF pathway and it is a standard care for metastatic clear cell renal cell carcinoma (ccRCC), although data supporting its use in ChRCC is much more limited. A 56-year-old underwent palliative nephrectomy for locally-advanced ChRCC with sarcomatoid differentiation. Tumor gene expression profiling using Affymetrix HG-U133 Plus 2.0 GeneChip platform demonstrated significantly elevated VEGF-C expression compared to normal renal tissue n=12 and other types RCC n=158. Adjuvant sunitinib was used to treat his residual unresectable retroperitoneal lymph nodes. He demonstrated an exceptional response and underwent complete surgical resection four months later. He has been managed with TKIs for nearly nine years with only minimal disease progression. Additional studies exploring treatment options for patients with non-clear cell RCC are needed; in their absence, we would recommend TKIs for patients whose tumors bear a similar molecular profile.

Abstract 1693: Nicotinamide N-methyltransferase in clear cell renal cell carcinoma primary tumors and metastases

2016 ◽  
Author(s):  
Anna Reustle ◽  
Steffen Rausch ◽  
Stefan Winter ◽  
Florian Büttner ◽  
Stephan Kruck ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Primary Tumors

Tyrosine kinase inhibitor-induced vasculopathy in clear cell renal cell carcinoma: an unrecognized antitumour mechanism

2013 ◽  
Vol 64 (4) ◽  
pp. 484-493 ◽  
Author(s):  
Toyonori Tsuzuki ◽  
Naoto Sassa ◽  
Yoshie Shimoyama ◽  
Takamitsu Morikawa ◽  
Ryoichi Shiroki ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma

Overcoming sunitinib-induced resistance by dose escalation in renal cell carcinoma: Evidence in animal models and patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4582-4582 ◽  
Author(s):  
Roberto Pili ◽  
Remi Adelaiye ◽  
Kiersten Marie Miles ◽  
Eric Ciamporcero ◽  
Paula Sotomayor ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Induced Resistance ◽  
Dose Escalation ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Vegf Receptor ◽  
Cell Renal Cell Carcinoma ◽  
Human Patient

4582 Background: Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). However, despite the clinical efficacy, eventually tumors develop resistance and progress. Thus, we have tested the hypothesis whether sunitinib dose-escalation could overcome initial drug resistance. Methods: Human patient-derived ccRCC xenografts were implanted in SCID mice and were randomly assigned into two groups (sunitinib and vehicle). Mice were treated with sunitinib 5 days/week with a dose-escalation schema starting from 40 mg/kg to 60 mg/kg and 80 mg/kg. Tumor volumes and body weights were assessed weekly. Tumor tissues and blood were collected prior to dose increments. In selected patients treated with 50 mg sunitinib and presenting minimal toxicities, dose was escalated to 62.5 and 75 mg at the time of tumor progression. Results: Our preclinical results show that patient-derived tumors (RP-01 and RP-02), although initially responsive to sunitinib 40 mg/kg, eventually became resistant to treatment. Following dose increase to 60 mg/kg, we observed again tumor response but eventually the tumors became resistant. A similar effect was noticed when we further escalated sunitinib to 80 mg/kg. Immunohistochemistry analysis shows decreased tumor vascularization during response to sunitinib, but then hypervascularization at the time of resistance. Associated increase in expression of the methyltransferase EZH2, the histone marks H3K27me3, H3k4me2 and H3K9me2 in tumors resistant to sunitinib was observed. Analysis of sunitinib and VEGF/VEFGR2 blood and tumor levels will be reported. In parallel, our clinical experience shows that intra-patient sunitinib dose-escalation was safe and clinical benefit was observed. Details on tumor responses and toxicities will be reported. Conclusions: Overall, our results suggest that sunitinib-induced resistance may be overcome in part by increasing the dose of the VEGF receptor tyrosine kinase inhibitor in mouse models and ccRCC patients, and highlights the potential role of epigenetic changes associated with sunitinib resistance.

STAT-3 and Β-catenin expression in metastatic clear cell renal cell carcinoma (mRCC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 583-583
Author(s):  
Aline Fusco Fares ◽  
Isabela Cunha ◽  
Daniel Vilarim Araujo ◽  
Leonardo de Azevedo Boente ◽  
Daniel Garcia ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Systemic Therapy ◽  
Renal Cell ◽  
Clear Cell ◽  
Antiangiogenic Therapy ◽  
Prognostic Scores ◽  
Cancer Center ◽  
Cell Renal Cell Carcinoma ◽  
Prognostic Criteria

583 Background: In mRCC, there are no prospectively validated biomarkers to guide the treatment and therapy decision is based on prognostic scores and histology. STAT-3 and Wnt/b-cateninare cell proliferation pathways and have already been related to prognostic in renal cell carcinoma. Objective: to evaluate the role of STAT-3 and b-catenin expression as prognostic biomarkers in clear cell mRCC. Methods: 684 medical records of renal cell carcinoma patients treated at AC Camargo Cancer Center from 2007 to 2015 were reviewed. 86 out of 684 patients fulfilled the study criteria: metastatic clear cell carcinoma, no sarcomatoid features, previous systemic therapy, previous nephrectomy and available tumor specimens from metastatic site. Pathological samples were arranged in a TMA. The number of positive stainings cells for each antibody in each core was categorized as low positive or negative versus highly positive expression. Results: We had available tissue blocks from 47 tumors. 32/45 patients (71,1%) had highly positive membrane b-catenin and none of the patients was positive for nuclear b-catenin. 27 /45 (60%) were categorized as low positive or negative STAT-3. There was no statistically significant association between STAT-3 and b-catenin expression with clinical prognostic criteria (MSKCC and Heng criteria). In the multivariate analysis, KPS < 80% (p = 0.02; HR: 2.7), time from nephrectomy to metastasis < 1 year (p = 0.04; HR: 2.1), no hypothyroidism (p = 0.05; HR: 2.4) and MSKCC criteria (p = 0.02; HR: 2.5) were confirmed as negative prognostic factors. Associative analysis showed that none of the patients with negative membrane b-catenin had response to systemic therapy (p=0.02). OS was 35.5 months (IC 22.2-48.8) and PFS was 12.5 months (IC 10.0-14.0). Conclusions: in our cohort, STAT-3 and B-catenin expression are not associated with the prognostic criteria (MSKCC and Heng). The loss of B-catenin expression is associated to a worse response rate to antiangiogenic therapy in metastatic clear cell renal cancer. [Table: see text]

scholarly journals Clinical and morphological features, immune profile of renal cell tumors with clear cytoplasm

2019 ◽  
Vol 15 (3) ◽  
pp. 126-131
Author(s):  
Yu. I. Osmanov ◽  
E. A. Kogan ◽  
L. O. Severgina ◽  
L. M. Rapoport ◽  
N. S. Aleksandrov ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Malignant Neoplasms ◽  
Kidney Tumors ◽  
Cell Renal Cell Carcinoma ◽  
Immunohistochemical Markers ◽  
Diagnostic Difficulties ◽  
Clear Cytoplasm

In the structure of oncological morbidity, renal cell carcinoma takes the 10th place among malignant neoplasms. The increase in incidence is observed from the age of 35–40 years and reaches a maximum at the age of 65–70 years. In terms of frequency of occurrence, clear cell renal cell carcinoma is ranked first among all kidney tumors. Meanwhile, due to the high heterogeneity of renal cell carcinomas with clear cytoplasm group, significant differential diagnostic difficulties arise in the morphological verification of these tumors. The article presents all nosological forms of kidney tumors with clear cytoplasm and provides a database of already known immunohistochemical markers for each nosological unit.

Chromosome 14q imbalances and pathways associated with resistance to antiangiogenic therapy in clear cell renal cell carcinoma.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 339-339 ◽  
Author(s):  
E. Jonasch ◽  
K. Alvarez ◽  
L. Peterson ◽  
N. M. Tannir ◽  
K. Sircar ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Antiangiogenic Therapy ◽  
Fisher Exact Test ◽  
Antiangiogenic Agents ◽  
Cell Renal Cell Carcinoma ◽  
Chromosomal Imbalances ◽  
Chromosome 14Q

339 Background: Antiangiogenic agents are used to treat metastatic clear cell renal cell carcinoma (ccRCC). Currently there are no biomarkers of therapeutic efficacy for these agents. Hypoxia inducible factor (HIF) alpha ratios have been linked to phenotypically distinct ccRCC subpopulations. The HIF1 alpha gene is located on chromosome 14q. In this study, the goal was to determine whether chromosomal imbalances identified with SNP arrays are linked to HIF ratios, and to clinical outcome. Methods: We obtained archival FFPE tumor specimens from 56 patients with mRCC treated with sorafenib or bevacizumab. DNA from the FFPE blocks was analyzed with Affymetrix 250K Nsp SNP microarrays. We identified the presence of genomic imbalances and loss of heterozygosity (LOH) to obtain virtual karyotypes. We then evaluated candidate genes in gain/lost chromosomal regions by qPCR and immunohistochemistry (IHC) in the bevacizumab treated specimens. Results: In the bevacizumab cohort, HIF1-alpha containing14q loss showed a significant association with worse response to treatment (CR/ PR vs. SD/PD, Fisher exact test, p = 0.0473). In addition, HIF1A mRNA expression was significantly reduced in all samples with 14q loss and was associated with PFS (HR = 2.29, 95% CI = 1.01-5.16, p = 0.045). HIF-1alpha protein expression was also reduced in samples with 14q loss. Conclusions: Chromosomal imbalances are associated with outcomes in ccRCC patients treated with antiangiogenic agents, and can lead to changes in gene expression. Low HIF1A expression was strongly correlated with shorter PFS. We hypothesize that loss of 14q could lead to an imbalance in HIF-1alpha/HIF-2alpha activity, leading to increased HIF-2alpha and enhanced c-Myc expression, which improves tumor cell viability and engenders resistance to cellular stress induced by antiangiogenic therapy. No significant financial relationships to disclose.

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