Soluble isoforms of vascular endothelial growth factor are predictors of response to sunitinib in metastatic renal cell carcinomas

Abstract

Background: Angiogenesis is the target of several agents in the treatment of malignancies, including renal cell carcinoma (RCC). There is a real need for surrogate biomarkers that can predict selection of patients who may benefit from antiangiogenic therapies, prediction of disease outcome and which may improve the knowledge regarding mechanism of action of these treatments. Tyrosine kinase inhibitors (TKI) have proven efficacy in metastatic RCC (mRCC). However, the molecular mechanisms underlying the clinical response to these drugs remain unclear.

Methodology/principal findings: The present study aimed to identify molecular biomarkers associated with the response to sunitinib, a Tyrosine kinase inhibitor. To evaluate this relationship, primary tumors from 23 metastatic RCC patients treated by sunitinib were analyzed for a panel of 16 biomarkers involved in tumor pathways targeted by sunitinib, using real-time quantitative reverse-transcriptase PCR. Nine of the 23 patients (39%) responded to sunitinib. Among transcripts analyzed, only the levels of vascular endothelial growth factor (VEGF) soluble isoforms (VEGF(121) and VEGF(165)) were associated with the response to sunitinib (P = 0.04 for both). Furthermore, the ratio of VEGF soluble isoforms (VEGF(121)/VEGF(165)) was significantly associated with prognosis (P = 0.02).

Conclusions: This preliminary study provides a promising tool that might help in the management of metastatic RCC, and could be extended to other tumors treated by TKI.

Figure 1. Boxplot of four RNA expression levels (in log₁₀ scale) according to treatment response.

The expression levels of interesting transcripts were normalized to the housekeeping PPIA (peptidylprolyl isomerase A) and TBP (TATA-box binding protein) gene transcripts. Since there was no difference between control genes, results were presented as copies of target gene per copy of PPIA. The median values and their corresponding logarithmic values in brackets were respectively: for VEGF₁₂₁ PR 1222 (7.1), SD 425 (6.0) and Failure 241 (5.4); and for VEGF₁₆₅ PR 905 (6.8), SD 460 (6.1) and Failure 352 (5.8). (*) for p<0.05.

Figure 2. Immunohistochemical staining of total VEGF protein in sections of human RCC tissues.

Representative RCC tumor center (left) and margins (right) with lower and strong expression of VEGF respectively.

Figure 3. Kaplan-Meier survival curve according to the ratio VEGF₁₂₁/VEGF_165.