Glioblastoma (GBM) has a median survival of less than 2 years due to intra-tumoral and inter-patient heterogeneity, diffuse infiltration of adjacent brain tissue, and absence of effective therapies. Development of more efficacious therapies will require better GBM models for the testing and identification of novel agents; traditional 2D cell culture lacks biologic and clinical fidelity and orthotopic xenograft models are costly, low throughput, and time consuming. We have developed a complex, patient-specific 3D cultured GBM model to assay drug response that combines high-throughput drug response determination with neurosphere formation and next-generation sequencing (NGS). Neurosphere formation and the presence/quality of glioblastoma stem cells (GSCs) has been validate through limited dilution growth in vivo. Our 3D model system has been validated against the primary patient GBM tissue and/or patient-derived xenografts (PDX) and consists of histology, epigenetic and mRNA expression analysis, and comparison of in vivo drug response. This strategy enabled examination of MGMT methylation in relation to temozolomide response, and possible actionable genetic mutations with candidate targeted therapies. Using our 3D model, we have observed EGFR-amplified GBM sensitivity to the EGFR inhibitor afatanib, and PTEN mutant GBM sensitivity to dual PI3K/mTOR inhibitor dactolisib. These data suggest validation of clinical and molecular correlation with this new in vitro, patient-derived 3D GBM model for drug response profiling. Our data supports the further development and use of complex 3D models, neurosphere formation, and NGS profiling for patient-specific GBM analysis. This model system is currently being considered for preclinical assessment of novel therapies and may be a useful adjunct in future precision medicine applications to improve patient outcomes.
Citation Format: Teresa DesRochers, Ashley Clark, Lauren O'Donnell, Qi Guo, Lillia Holmes, Lacey Dobrolecki, Michael Lewis, David Schammel, Jeff Edenfield, Charles Kanos, Fred Nelson, Steve Gardner, Michael Lynn, Philip Hodge, Christopher Corless, Paul Clark, Hal E. Crosswell, John Kuo. Development of an in vitro 3D glioblastoma model system for patient-specific drug response profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4837. doi:10.1158/1538-7445.AM2017-4837