Preclinical Models of Pediatric Brain Tumors—Forging Ahead

Abstract

Approximately five out of 100,000 children from 0 to 19 years old are diagnosed with a brain tumor. These children are treated with medication designed for adults that are highly toxic to a developing brain. Those that survive are at high risk for a lifetime of limited physical, psychological, and cognitive abilities. Despite much effort, not one drug exists that was designed specifically for pediatric patients. Stagnant government funding and the lack of economic incentives for the pharmaceutical industry greatly limits preclinical research and the development of clinically applicable pediatric brain tumor models. As more data are collected, the recognition of disease sub-groups based on molecular heterogeneity increases the need for designing specific models suitable for predictive drug screening. To overcome these challenges, preclinical approaches will need continual enhancement. In this review, we examine the advantages and shortcomings of in vitro and in vivo preclinical pediatric brain tumor models and explore potential solutions based on past, present, and future strategies for improving their clinical relevancy.

Advanced Spheroid, Tumouroid and 3D Bioprinted In-Vitro Models of Adult and Paediatric Glioblastoma

“…The location of GBM is a significant barrier to successful treatment. As well as making surgical resection difficult, the extracellular matrix (ECM) composition [ 23 , 24 ], tissue mechanics [ 15 , 25 ] and stromal-cell interactions [ 26 , 27 , 28 ] within the brain elicit unique tumour qualities. The brain provides tissue niches for stem-like cancer stem cells (CSC s ) and hypoxic regions develop, which further enables drug resistance and recurrence [ 29 , 30 ].…”

“…The caveats of mouse models are that tumours can take months to establish [ 72 ] and mice are commonly immunocompromised [ 73 ]. Humanised [ 25 ] and AVATAR mouse models [ 44 ] can address some of these issues, but ethical considerations prevent the use of animal models for high-throughput drug screening. There are published works that utilise mouse models for p GBM [ 37 , 69 ] and DMG [ 13 , 74 ] research, but for reasons stated above, the use of such mouse models is not the best solution for some applications.…”

Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

“…Recent advancements in molecular profiling have vastly improved our understanding of pediatric high-grade glioma and have identified unique genetic and epigenetic features of pHGG which had been previously conflated with adult gliomas. Several pathways and molecular alterations were identified in hemispherical pHGG, including the PI3K/AKT, Ras-Raf-MEK-ERK, RB, and p53 pathways [ 14 , 15 , 16 , 17 , 18 ] ( Figure 1 ). Most notably, the discovery of recurrent mutations in the genes encoding histone variants H3.3 (H3F3A) and H3.1 (HIST1H3B/C) demonstrated the unique biology of pediatric brain tumors [ 10 , 19 , 20 ] ( Figure 2 ).…”

Towards Immunotherapy for Pediatric Brain Tumors

“…Further, these experiments are performed in immunodeficient mouse models to allow tumor engraftment. By contrast, genetically engineered models, developed by introducing specific genetic driver mutations into the relevant cell of origin, may provide valuable insights into tumor initiation in the native microenvironment, and allow tumor modeling in immunocompetent animals [70]. For example, this has been evident in a mouse model of medulloblastoma, a brain tumor with four distinct molecular subtypes.…”