title: Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma.
abstract: Real-time monitoring of drug efficacy in glioblastoma multiforme (GBM) is a major clinical problem as serial re-biopsy of primary tumours is often not a clinical option. MGMT (O(6)-methylguanine DNA methyltransferase) and APNG (alkylpurine-DNA-N-glycosylase) are key enzymes capable of repairing temozolomide-induced DNA damages and their levels in tissue are inversely related to treatment efficacy. Yet, serial clinical analysis remains difficult, and, when done, primarily relies on promoter methylation studies of tumour biopsy material at the time of initial surgery. Here we present a microfluidic chip to analyse mRNA levels of MGMT and APNG in enriched tumour exosomes obtained from blood. We show that exosomal mRNA levels of these enzymes correlate well with levels found in parental cells and that levels change considerably during treatment of seven patients. We propose that if validated on a larger cohort of patients, the method may be used to predict drug response in GBM patients.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, Massachusetts 02114, USA.
authors.forename: Huilin
authors.initials: H
authors.lastname: Shao
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, Massachusetts 02114, USA.
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Chung
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, Massachusetts 02114, USA.
authors.forename: Kyungheon
authors.initials: K
authors.lastname: Lee
authors.affiliation: 1] Department of Neurology, Massachusetts General Hospital, Fruit St, Boston, Massachusetts 02114, USA [2] Program in Neuroscience, Harvard Medical School, 200 Longwood Ave, Boston, Massachusetts 02115, USA.
authors.forename: Leonora
authors.initials: L
authors.lastname: Balaj
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, Massachusetts 02114, USA.
authors.forename: Changwook
authors.initials: C
authors.lastname: Min
authors.affiliation: Division of Neurological Surgery, UCSD School of Medicine, San Diego, California 92103, USA.
authors.forename: Bob S
authors.initials: BS
authors.lastname: Carter
authors.affiliation: 1] Division of Neurological Surgery, UCSD School of Medicine, San Diego, California 92103, USA [2] Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Hochberg
authors.affiliation: 1] Department of Neurology, Massachusetts General Hospital, Fruit St, Boston, Massachusetts 02114, USA [2] Program in Neuroscience, Harvard Medical School, 200 Longwood Ave, Boston, Massachusetts 02115, USA [3] Department of Radiology, Massachusetts General Hospital, Fruit St, Boston, Massachusetts 02114, USA.
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
authors.affiliation: 1] Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, Massachusetts 02114, USA [2] Department of Radiology, Massachusetts General Hospital, Fruit St, Boston, Massachusetts 02114, USA.
authors.forename: Hakho
authors.initials: H
authors.lastname: Lee
authors.affiliation: 1] Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, Massachusetts 02114, USA [2] Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA [3] Department of Radiology, Massachusetts General Hospital, Fruit St, Boston, Massachusetts 02114, USA [4] Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, Massachusetts 02115, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D055354:Exosomes / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D018189:Immunomagnetic Separation; D008819:Mice, Nude; D044085:Microfluidics / Q000379:methods*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D003606:Dacarbazine; D000077204:Temozolomide