This study will evaluate the use of RNA in serum exosomes as biomarkers for cancer. Exploration of this new technology will be carried out in a clinical research study on glioma patients, based on our studies demonstrating that serum/plasma exosomes from glioblastoma patients are derived from tumors and contain mutant RNAs and relative levels of mRNAs and microRNAs distinctive to those tumors. Gliomas are the most common type of primary brain tumor in humans occurring at an incidence of about 3 cases/100,000 individuals per year with a 5 year survival rate of about 3%. Treatment is confounded as diagnosis depends on neurosurgical biopsy and pathologic analysis. Once removal of the main tumor mass has been carried out patients are monitored by MRI and neurologic symptoms for signs of tumor regrowth, both of which can give false-positives due to residual effects of brain surgery and chemical/radiation treatment. Our findings are the first to support RNA serum biomarkers which have the potential to report on the presence, burden and classification of distinct subtypes of glioma tumors, i.e. EGFRvIII. This distinctive mutant/variant for glioblastoma, EGFRvIII mRNA in serum exosomes from these patients can in itself be the basis for a marketable product which can inform the clinical status and prognosis of patients, as well as indicate appropriate drug treatments and track therapeutic responses. The objectives of this study will be: 1) to optimize methods for collection and storage of serum/plasma, and isolation of exosomes in order to obtain high yields and integrity of RNA;2) to determine whether the mutant/variant EGFRvIII mRNA in serum/plasma exosomes can serve as a marker of tumor burden and/or progression in glioma patients;and 3) to initiate a systematic assessment of other known genetic changes i gliomas which can be detected in serum/plasma exosomes of the patients.

Public Health Relevance

is study will evaluate the use of RNA in serum exosomes as biomarkers for cancer. Our previous studies have demonstrated that serum exosomes from glioblastoma patients are derived from tumors and contain mutant RNAs and upregulated levels of mRNAs and microRNAs distinctive to these tumors. We will focus on optimization of this technology and relevance for tumor burden and recurrence in glioma patients. This technology has wide applications as most types of cancer also release exosomes into the serum and have distinguishing RNA features.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA141226-02
Application #
7845592
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Lively, Tracy (LUGO)
Project Start
2009-06-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$194,700
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Balaj, Leonora; Atai, Nadia A; Chen, Weilin et al. (2015) Heparin affinity purification of extracellular vesicles. Sci Rep 5:10266
Atai, Nadia A; Balaj, Leonora; van Veen, Henk et al. (2013) Heparin blocks transfer of extracellular vesicles between donor and recipient cells. J Neurooncol 115:343-51
Chen, Walter W; Balaj, Leonora; Liau, Linda M et al. (2013) BEAMing and Droplet Digital PCR Analysis of Mutant IDH1 mRNA in Glioma Patient Serum and Cerebrospinal Fluid Extracellular Vesicles. Mol Ther Nucleic Acids 2:e109
Balaj, Leonora; Lessard, Ryan; Dai, Lixin et al. (2011) Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2:180