Advances in the fight against brain cancer provide new opportunities to """"""""personalize"""""""" and improve drug treatment of patients. These have included genome sequencing of hundreds of glioblastoma (GBM) tumors, pathway analysis of upregulated mRNAs, increasing sophistication of drug design to target driver mutations, and the discovery that tumors release exosomes into the circulation that manifest the genotype of individual tumors. This proposal will expand the informational content of a Phase II drug trial for GBM to include a research arm to monitor the genetic status of the tumors in individual patients over time using specific mutations and levels of mRNA and miRNA in serum exosomes as biomarkers. These biomarkers have the potential to elucidate which genetic changes in tumors make patients more responsive to a specific drug, whether compensatory genetic changes occur in the tumor during treatment, and how these influence the overall response to therapy. This clinical trial will evaluate a novel irreversible inhibitor of a kinase signaling pathway which is activated by alterations in the epidermal growth factor receptor (EGFR) in GBM patients. The cohort will consist of recurrent patients with verified EGFR amplification based on tumor biopsies. A subset of tumor samples will be analyzed for mutations in genomic DNA in 17 cancer driver genes by the Molecular Pathology Service - in parallel we will monitor a number of genetic parameters critical for GBM growth in RNA from longitudinal serum exosome samples from 56 patients in this study, all of whom will concurrently have a full clinical workup. All samples will be biobanked and of sufficient size to allow multiple additional assays in future studies. Statistical analysis will be carried out to evaluate correlations between genetic status of tumors and radiographic assessment of tumor volume, progression-free survival and overall survival. We predict that the constellation of genetic changes in individual GBM tumors can predict their susceptibility to specific drugs and that response to drug treatment can be monitored by analysis of RNA from circulating tumor exosomes.
This proposal will evaluate a new biomarker technology to monitor sensitivity and response to cancer therapy. RNA isolated from tumor-derived serum microvesicles will be used to correlate changes in the genetic profile with clinical response to a new irreversible tyrosine kinase inhibitor.
|Balaj, Leonora; Atai, Nadia A; Chen, Weilin et al. (2015) Heparin affinity purification of extracellular vesicles. Sci Rep 5:10266|
|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|
|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|