Abstract

There is a compelling need for new therapeutic strategies for glioblastoma multiforme (GBM). Preclinical target and therapeutic discovery for GBMs is primarily conducted using cell lines grown in serum-containing media, such as U-87 MG, which do not reflect the gene expression profiles of tumors found in GBM patients. To address this lack of representative models, we sought to develop a panel of patient-derived GBM models and characterize their genomic features, using RNA sequencing (RNA-seq) and growth characteristics, both when grown as neurospheres in culture, and grown orthotopically as xenografts in mice. When we compared these with commonly used GBM cell lines in the Cancer Cell Line Encyclopedia (CCLE), we found these patient-derived models to have greater diversity in gene expression and to better correspond to GBMs directly sequenced from patient tumor samples. We also evaluated the potential of these models for targeted therapy, by using the genomic characterization to identify small molecules that inhibit the growth of distinct subsets of GBMs, paving the way for precision medicines for GBM.

Highlights

  • Glioblastoma multiforme is the most common form of primary brain cancer in adults and is a deadly disease associated with extremely poor prognoses [1]

  • When we compared these with commonly used glioblastoma multiforme (GBM) cell lines in the Cancer Cell Line Encyclopedia (CCLE), we found these patient-derived models to have greater diversity in gene expression and to better correspond to GBMs directly sequenced from patient tumor samples

  • We evaluated the potential of these models for targeted therapy, by using the genomic characterization to identify small molecules that inhibit the growth of distinct subsets of GBMs, paving the way for precision medicines for GBM

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Summary

Introduction

Glioblastoma multiforme is the most common form of primary brain cancer in adults and is a deadly disease associated with extremely poor prognoses [1]. It has been shown that GBM cancer cell lines cultured with serum poorly represent the gene expression profile and physiology of GBM tumors in patients, and exhibit considerable divergence from the original tumors from which they were derived [4]. We have previously demonstrated that glioblastoma-patient-derived neurosphere cultures (serumfree) are able to preserve the parental tumor somatic mutations and copy number alterations, including extrachromosomal oncogene amplification [5]. We sought to extend the usefulness of these models by analyzing the gene expression profiles and mutation status of these patient-derived models www.oncotarget.com using RNA sequencing. We have found through RNA sequencing of GBM neurospheres that we can predict sensitivity to small molecule inhibitors in some cases, paving the way for novel targeted therapies in GBM

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