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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy
L del Puerto-Nevado1, F Rojo2, S Zazo2
1Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital 'Fundación Jiménez Díaz', Avenida Reyes Católicos, 2, 28040 Madrid, Spain.
Background:
Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients.
Methods:
Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out.
Results:
The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10-300); for KDR 258.5 (range, 150-300); for pKDR-Y1775 10.8 (range, 0-65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10-126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49-19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25-21.05).
Conclusions:
Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients.
Insights
Phosphorylated KDR (p-KDR) in tumor stroma can predict treatment response in metastatic renal cell carcinoma patients receiving sunitinib. This biomarker may help identify patients likely to benefit from sunitinib therapy.
Area of Science:
- Oncology
- Molecular Biology
- Translational Research
Background:
- Sunitinib is a standard treatment for metastatic renal cell carcinoma (mRCC).
- A subset of patients experiences toxicity without clinical benefit from sunitinib.
- Predictive biomarkers are needed to personalize treatment decisions.
Purpose of the Study:
- To evaluate key molecular targets involved in angiogenesis as predictive biomarkers for sunitinib treatment in mRCC.
- To assess the potential of VEGF-A, KDR, p-KDR, and MVD to predict clinical benefit.
Main Methods:
- Immunohistochemistry was used to determine VEGF-A, KDR, p-KDR-Y1775, and CD31 (for MVD) expression in 48 RCC patients (23 treated with sunitinib).
- Thresholds were established for each biomarker.
- Univariate and multivariate analyses were performed for progression-free survival (PFS) and overall survival (OS).
Main Results:
- p-KDR-Y1775 expression showed statistically significant differences for PFS (P=0.01) and OS (P=0.007) in sunitinib-treated patients.
- p-KDR-Y1775 remained a significant independent predictor for PFS (P=0.01; HR: 5.35) and OS (P=0.02; HR: 5.13) in multivariate analysis.
- VEGF-A, total KDR, and MVD did not show significant predictive value.
Conclusions:
- Tumor stroma phosphorylated KDR (p-KDR) expression may serve as a predictive biomarker for clinical outcomes in first-line sunitinib-treated RCC patients.
- p-KDR could help identify patients who will achieve clinical benefit from sunitinib.
- This finding supports the potential for targeted therapy selection based on molecular profiling.
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