title: Dynamics of circulating hypoxia-mediated miRNAs and tumor response in patients with high-grade glioma treated with bevacizumab.
abstract: OBJECTIVE Bevacizumab is an antiangiogenic agent under investigation for use in patients with high-grade glioma. It produces a high rate of radiological response; however, this response should be interpreted with caution because it may reflect normalization of the tumor vasculature and not necessarily a true antitumor effect. The authors previously demonstrated that 4 hypoxia-mediated microRNAs (miRNA)-miR-210, miR-21, miR-10b, and miR-196b-are upregulated in glioma as compared with normal brain tissue. The authors hypothesized that the regulation and expression of these miRNAs would be altered in response to bevacizumab treatment. The object of this study was to perform longitudinal monitoring of circulating miRNA levels in patients undergoing bevacizumab treatment and to correlate it with tumor response. METHODS A total of 120 serum samples from 28 patients with high-grade glioma were prospectively collected prior to bevacizumab (n = 15) or temozolomide (TMZ; n = 13) treatment and then longitudinally during treatment. Quantification of the 4 miRNAs was evaluated by real-time polymerase chain reaction using total RNA extracted from the serum. At each time point, tumor response was assessed by Response Assessment in Neuro-Oncology criteria and by performing MRI using fluid attenuated inversion recovery (FLAIR) and contrast-enhanced images. RESULTS As compared with pretreatment levels, high levels of miR-10b and miR-21 were observed in the majority of patients throughout the bevacizumab treatment period. miR-10b and miR-21 levels correlated negatively and significantly with changes in enhancing tumor diameters (r = -0.648, p < 0.0001) in the bevacizumab group but not in the TMZ group. FLAIR images and the RANO assessment did not correlate with the sum quantification of these miRNAs in either group. CONCLUSIONS Circulating levels of miR-10b and miR-21 probably reflect the antiangiogenic effect of therapy, but their role as biomarkers for tumor response remains uncertain and requires further investigation.
authors.affiliation: Center for Neuro-Oncology, Davidoff Institute of Oncology, Rabin Medical Center, Campus Beilinson, Petach Tikva.|Leslie and Michael Gaffin Center for Neuro-Oncology and Department of Neurology, The Agnes Ginges Center for Human Neurogenetics.
authors.forename: Tali
authors.initials: T
authors.lastname: Siegal
authors.affiliation: Leslie and Michael Gaffin Center for Neuro-Oncology and Department of Neurology, The Agnes Ginges Center for Human Neurogenetics.
authors.forename: Hanna
authors.initials: H
authors.lastname: Charbit
authors.affiliation: Department of Neurosurgery, Hadassah Hebrew University Medical Center, Jerusalem, Israel; and.
authors.forename: Iddo
authors.initials: I
authors.lastname: Paldor
authors.affiliation: Leslie and Michael Gaffin Center for Neuro-Oncology and Department of Neurology, The Agnes Ginges Center for Human Neurogenetics.
authors.forename: Bracha
authors.initials: B
authors.lastname: Zelikovitch
authors.affiliation: Leslie and Michael Gaffin Center for Neuro-Oncology and Department of Neurology, The Agnes Ginges Center for Human Neurogenetics.
authors.forename: Tamar
authors.initials: T
authors.lastname: Canello
authors.affiliation: Leslie and Michael Gaffin Center for Neuro-Oncology and Department of Neurology, The Agnes Ginges Center for Human Neurogenetics.
authors.forename: Arriel
authors.initials: A
authors.lastname: Benis
authors.affiliation: Departments of 4 Neurosurgery and.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Wong
authors.affiliation: Departments of 4 Neurosurgery and.|Surgery, The Royal Melbourne Hospital and The University of Melbourne, Australia.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morokoff
authors.affiliation: Departments of 4 Neurosurgery and.|Surgery, The Royal Melbourne Hospital and The University of Melbourne, Australia.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Kaye
authors.affiliation: Leslie and Michael Gaffin Center for Neuro-Oncology and Department of Neurology, The Agnes Ginges Center for Human Neurogenetics.
authors.forename: Iris
authors.initials: I
authors.lastname: Lavon
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D000074166:Circulating MicroRNA / Q000097:blood*; D005260:Female; D005910:Glioma / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000860:Hypoxia; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011446:Prospective Studies
chemical_list: D020533:Angiogenesis Inhibitors; D000074166:Circulating MicroRNA; D000068258:Bevacizumab
keywords: FLAIR = fluid attenuated inversion recovery; GBM = glioblastoma multiforme; HIF-1 = hypoxia-inducible factor-1; PCR = polymerase chain reaction; RANO = Response Assessment in Neuro-Oncology; RQ = relative quantification; TMZ = temozolomide; VEGF = vascular endothelial growth factor; antiangiogenic therapy; bevacizumab; circulating biomarkers; glioblastoma; high-grade glioma; miRNA = microRNA; microRNA; oncology; temozolomide