Blood-based assays for the detection of glioblastoma RNA biomarkers

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 DESCRIPTION (provided by applicant): Gliomas account for about 60% of all primary central nervous system tumors. Glioblastoma (GBM or grade IV glioma), which comprises 51.2% of all gliomas, is the most malignant form. Over the last two decades, the major breakthrough in the treatment for GBM has been the addition of the DNA alkylating agent temozolomide (TMZ) to the standard of care including surgery and radiation yielding an increase in the median survival from 12.1 months to 14.6 months; however, as the poor survival rate indicates, these treatments have not been effective in preventing disease progression. It is now clear that first-line treatmen for patients with GBM will become more tailored according to (epi)genetic subtypes. The potent effect of EGFRvIII peptide vaccination (CDX-110; Rindopepimut) in early phase clinical trials in patients with GBM harboring EGFRvIII mutation (present in 35% of patients) is a perfect example of such a tailored treatment. Median progression-free survival (PFS) and overall survival (OS) were significantly higher than in matched historical controls. One of the main barriers to these targeted therapies is obtaining easily accessible high-quality nucleic acids for diagnostic analysis. Typically, EGFRvIII profiling is performed at the time of surgery on resected GBM tumor tissues, however, this method is invasive and does not allow monitoring of EGFRvIII (and other biomarkers) longitudinally during the course of therapy. Recently, our team has demonstrated that thrombocytes and extracellular vesicles isolated from blood of GBM patients contain tumor-derived RNA biomarkers, including EGFRvIII, that correlates with EGFRvIII expression in tissue biopsies. Thus, RNA of thrombocytes and extracellular vesicles may serve as a readily accessible platform for biomarker detection, overcoming problems of tumor heterogeneity and sampling error as observed for biopsy analysis. In this proposal, we will evaluate thrombocytes and microvesicles as a non-invasive companion diagnostics test for the detection of glioblastoma biomarkers using quantitative assays. Further, we will use these platforms to monitor EGFRvIII status longitudinally, and thus patient response to EGFRvIII-targeted vaccine. If successful, this method could have a broad application for different cancer types in which personalized therapy is being evaluated.