Angiogenic molecular signature in colorectal cancer: Pharmacogenomic implications for the use of antiangiogenic therapies

Abstract

In the framework of personalized medicine in antiangiogenesis, we took a translational research approach to explore the angiogenic molecular signature of advanced CRC patients. As derived from our findings in vitro, the tumour microenvironment of CRC metastases would be different to that of primary tumours. The mCRC more aggressive molecular phenotype provides some intrinsic resistance to the hypoxic induction of VEGF expression. The distinct metastatic "secretome" emerge as potential prognostic markers and alternative intervention targets. The identification of predictive biomarkers for response to bevacizumab-based combination therapy allows a more informed therapeutic decision for patients with mCRC. Platelet-normalized serum circulating VEGF baseline levels are significantly lower in VEGF-2578AA and VEGF-460CC carriers; and low-VEGF levels-associated SNPs correlate with a better clinical outcome of TTP. A predictive risk score is calculated considering the Köhne low-risk category, DCR achievement and any favourable VEGF genotype, which renders four different risk groups. High serum levels of EGF and MDC and low levels of IL-10, IL-6 and IL-8 are associated with a higher likelihood of response to the bevacizumab-based combination therapy. A risk signature is calculated by summing-up the number of high-risk factors (below and above the median for EGF and MDC, and IL-10, IL-6 and IL-8, respectively) significantly correlates with progression and survival outcomes, improving single factor’s predictive ability. Exposure to the combination therapy reduces levels of IL-8 and increases levels of the protective MDC, findings which are in agreement with the reported roles for both cytokines inflammatory and angiogenesis mediators in colorectal cancer.