Preclinical models of glioblastoma: limitations of current models and the promise of new developments

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumour, yet little progress has been made towards providing better treatment options for patients diagnosed with this devastating condition over the last few decades. The complex nature of the disease, heterogeneity, highly invasive potential of GBM tumours and until recently, reduced investment in research funding compared with other cancer types, are contributing factors to few advancements in disease management. Survival rates remain low with less than 5% of patients surviving 5 years. Another important contributing factor is the use of preclinical models that fail to fully recapitulate GBM pathophysiology, preventing efficient translation from the lab into successful therapies in the clinic. This review critically evaluates current preclinical GBM models, highlighting advantages and disadvantages of using such models, and outlines several emerging techniques in GBM modelling using animal-free approaches. These novel approaches to a highly complex disease such as GBM show evidence of a more truthful recapitulation of GBM pathobiology with high reproducibility. The resulting advancements in this field will offer new biological insights into GBM and its aetiology with potential to contribute towards the development of much needed improved treatments for GBM in future.

Givinostat-Liposomes: Anti-Tumor Effect on 2D and 3D Glioblastoma Models and Pharmacokinetics

“…Although in vivo studies remain a fundamental step in cancer research, animals often do not represent a realistic model of GBM when human xenograft or orthotopic transplants are used. In fact, they are different than the original niche, do not show an infiltrative nature as human GBM does, and immunomodulatory therapies cannot be tested [ 60 , 61 ]. Moreover, mice do not exhibit endothelial proliferation and, more importantly, when xenograft transplantations are performed through subcutaneous injection, the local microenvironment is very different from the brain microenvironment, resulting in a lack of tumor growth [ 62 ].…”

Dynamic Interactions between Tumor Cells and Brain Microvascular Endothelial Cells in Glioblastoma

“…In 3D tumor platforms, the patient's tissue-derived cells are co-cultured with different cell populations in a gel-embedded system in order to mimic the complex TME, and then incubated in a classical growth medium [131,132]. In a different setting, cancer cells can be assembled within microfluidic devices, offering the great advantage of working with a reduced number of patient-derived cells.…”

“…In a different setting, cancer cells can be assembled within microfluidic devices, offering the great advantage of working with a reduced number of patient-derived cells. Furthermore, in mechanically supported 3D models, cells are layered in a solid scaffold made up of biomaterials with different mechanical properties and then maintained in a classical growth medium [131,132]. All of these models present different ECM components and different cell types in co-culture and are suitable for studying the interplay and crosstalk among tumor cells and TME cells.…”

“…High-throughput 3D models have the potential to fill the gap between the 2D in vitro and in vivo models [132]. Along with the benefits of their low cost and high reproducibility, they overcome several limitations of both the classical 2D cell cultures and in vivo models.…”

“…Although several 3D models have had great success in interrogating tumor responses to the TME (for a review: [131,132]), mainly regarding ECM composition, organization, and drug resistance and diffusion, only a few studies have investigated tumor cell-BMEC dynamics. In this regard, more recently, 3D vascularized tumoroid in vitro models con-firmed their validity in recapitulating the complex GBM milieu [136,137].…”