Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma

• Published in: Nature communications Vol. 6; no. 1; p. 6999
• Main Authors: Shao, Huilin, Chung, Jaehoon, Lee, Kyungheon, Balaj, Leonora, Min, Changwook, Carter, Bob S., Hochberg, Fred H., Breakefield, Xandra O., Lee, Hakho, Weissleder, Ralph
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-05-2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 38; 38/90; 631/1647/277; 692/308; 692/699/67/1059/2326; 692/699/67/1922; Animals; Biomarkers, Tumor; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Cell Line, Tumor; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Dacarbazine - therapeutic use; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Exosomes - drug effects; Exosomes - genetics; Exosomes - metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Glioblastoma - drug therapy; Glioblastoma - genetics; Humanities and Social Sciences; Humans; Immunomagnetic Separation; Mice, Nude; Microfluidics - methods; multidisciplinary; RNA, Messenger - genetics; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Treatment Outcome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7999

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
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-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.
Predicting and monitoring chemotherapy response remains a challenge for glioma treatment. Here the authors show that a microfluidic device can isolate glioma-derived exosomes from patient blood and accurately determine the levels of mRNA of key enzymes important for chemoresponsiveness.