A novel 3D human glioblastoma cell culture system for modeling drug and radiation responses

Abstract

Background.Glioblastoma (GBM) is the most common primary brain tumor, with dismal prognosis. The failure of drug–radiation combinations with promising preclinical data to translate into effective clinical treatments may relate to the use of simplified 2-dimensional in vitro GBM cultures.Methods.We developed a customized 3D GBM culture system based on a polystyrene scaffold (Alvetex) that recapitulates key histological features of GBM and compared it with conventional 2D cultures with respect to their response to radiation and to molecular targeted agents for which clinical data are available.Results.In 3 patient-derived GBM lines, no difference in radiation sensitivity was observed between 2D and 3D cultures, as measured by clonogenic survival. Three different molecular targeted agents, for which robust clinical data are available were evaluated in 2D and 3D conditions: (i) temozolomide, which improves overall survival and is standard of care for GBM, exhibited statistically significant effects on clonogenic survival in both patient-derived cell lines when evaluated in the 3D model compared with only one cell line in 2D cells; (ii) bevacizumab, which has been shown to increase progression-free survival when added to standard chemoradiation in phase III clinical trials, exhibited marked radiosensitizing activity in our 3D model but had no effect on 2D cells; and (iii) erlotinib, which had no efficacy in clinical trials, displayed no activity in our 3D GBM model, but radiosensitized 2D cells.Conclusions.Our 3D model reliably predicted clinical efficacy, strongly supporting its clinical relevance and potential value in preclinical evaluation of drug–radiation combinations for GBM.

Quantitative histopathologic assessment of perfusion MRI as a marker of glioblastoma cell infiltration in and beyond the peritumoral edema region

“…Such co‐option mechanisms, widely documented in clinical specimens, have been shown to compromise the efficacy of treatments that either target angiogenesis or promote vascular normalization or integrity in both primary and metastatic tumors. Consistent with the clinical context, G7 tumor cells have been shown to express VEGF both in vivo and in vitro; hence, angiopoiesis is expected close to the tumor core. Here, investigating at earlier stages of tumor development allowed minimizing the effects related to tumor angiogenesis or necrosis.…”

“…The animals were intracranially injected with G7 cells (10 5 cells per mouse) into the subventricular zone using stereotactic equipment. 20 Study outcomes are reported following the ARRIVE guidelines. 21 Ten animals were scanned 9 and 12 weeks after GBM cell injection.…”

Applications of cell culture studies in pharmaceutical technology

“…Gomez-Roman et al, 2017 tested temozolomide, bevacizumab and erlotinib on 2D and 3D Glioblastoma cultures. They proved that these three drugs affect 2D and 3D cultures and 3D model responses were similar to clinical trials 84 . In a recent study by Ribas et al, 2016, the authors created a vascular microenvironment of the heart for drug development 85 .…”

Three‐dimensional cell culture models for anticancer drug screening: Worth the effort?

“…However, this study underlines the need for better predictive in vitro models. Multiple studies suggest that drug responses of 2D cell cultures poorly predict the outcome of clinical studies (Aljitawi et al, 2014;Bhadriraju & Chen, 2002;Edmondson, Broglie, Adcock, & Yang, 2014;Gomez-Roman et al, 2017;Guengerich, 2007;Hingorani et al, 2009;Ramaiahgari et al, 2014;Ravi, Paramesh, Kaviya, Anuradha, & Solomon, 2015;Weaver et al, 1997).…”