CBM-15DYNAMICS OF CIRCULATING HYPOXIA MEDIATED miRNAs AND TUMOR RESPONSE IN HIGH-GRADE GLIOMA PATIENTS TREATED WITH BEVACIZUMAB

Abstract

BACKGROUND: Bevacizumab is an antiangiogenic agent which is approved for recurrent glioblastoma and is still under investigation in high-grade gliomas. It produces a high rate of radiologic response but this response should be interpreted with caution because it is related to normalization of permeable tumor vessels and not necessarily to a true anti-tumor effect. We previously demonstrated that four of the hypoxia-mediated-miRNAs (miR-210, miR-21, miR-10b and miR-196b), are up-regulated in gliomas as compared to normal brain. We hypothesized that the regulation and expression of these miRNAs will be altered in response to bevacizumab treatment and tested it prospectively. OBJECTIVES: To perform a longitudinal monitoring of the circulating miRNAs in patients exposed to bevacizumab treatment and to correlate it with tumor response. METHODS: 55 serum samples were prospectively collected from 15 high-grade glioma patients prior to bevacizumab treatment and longitudinally during treatment. The quantification of the 4 miRNAs was evaluated by real-time-RT-PCR using total RNA that was extracted from the serum. At each time point tumor response was assessed on MRI using FLAIR and contrast enhanced images as well as RANO criteria for tumor response. RESULTS: Serum quantification level of miR-210 and miR-196b did not differ in high-grade glioma patients from healthy controls while levels of miR-10b and miR-21 were significantly increased in untreated brain tumor patients. Throughout the period of bevacizumab treatment higher quantification levels were displayed for both miR-10b and miR-21 in the majority of patients when compared to pre-bevacizumab levels. Their quantification correlated negatively and significantly with changes in enhancing tumor diameters (R= -0.648, p < 0.0001). FLAIR images and RANO assessment did not correlate with the sum quantification of these miRNAs. CONCLUSIONS: Circulating miR-10b and miR-21 probably reflect the anti-angiogenic effect of therapy but their role as biomarkers for tumor response remains uncertain and requires further investigation.