Patient-Derived Orthotopic Xenograft Models of Pediatric Brain Tumors: In a Mature Phase or Still in Its Infancy?

Abstract

In recent years, molecular profiling has led to the discovery of an increasing number of brain tumor subtypes, and associated therapeutic targets. These molecular features have been incorporated in the 2016 new World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), which now distinguishes tumor subgroups not only histologically, but also based on molecular characteristics. Despite an improved diagnosis of (pediatric) tumors in the CNS however, the survival of children with malignant brain tumors still is far worse than for those suffering from other types of malignancies. Therefore, new treatments need to be developed, based on subgroup-specific genetic aberrations. Here, we provide an overview of the currently available orthotopic xenograft models for pediatric brain tumor subtypes as defined by the 2016 WHO classification, to facilitate the choice of appropriate animal models for the preclinical testing of novel treatment strategies, and to provide insight into the current gaps and challenges.

Modeling the developmental origins of pediatric cancer to improve patient outcomes

“…How do we move beyond in silico analyses or studies done with cell lines grown on plastic? Certainly xenografts, especially orthotopic and patient-derived xenografts, hold promise as potentially more accurate models ( Aparicio et al, 2015 ; Hermans and Hulleman, 2020 ; Zarzosa et al, 2017 ), although the overall rarity of most pediatric cancers can make it difficult to assemble large cohorts. In vitro , innovative spheroid culture approaches have begun to reveal dramatic changes in drug sensitivity of the same cells cultured in three-dimensional versus two-dimensional environments ( Breslin and O'Driscoll, 2016 ; Fujii et al, 2009 ; Imamura et al, 2015 ; Musah-Eroje and Watson, 2019 ; Polo et al, 2010 ).…”

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

“…Of note, while several groups have established PDXs from cortically based pediatric tumors [ 38 , 47 , 48 ], none of these have harbored H3.3G34R/V mutations. All published PDX models of histone-mutant pHGG are too numerous to specify here; however, they have been comprehensively catalogued in a recent review [ 41 ].…”

In Vivo and Ex Vivo Pediatric Brain Tumor Models: An Overview

“…Different immunocompromised mouse strains have various sensitivity to chemotherapy or radiation, which needs to be considered when choosing an appropriate animal model. For example, BALB/c mice are very sensitive to radiation and SCID mice are sensitive to γ-irradiation and thus are not useful for radiotherapy related studies ( 39 ). Immunodeficient mice can also be modified by receiving human bone marrow to reconstitute a human immune response.…”

“…Immunodeficient mice can also be modified by receiving human bone marrow to reconstitute a human immune response. These humanized mice provide an opportunity to even more closely recapitulate human brain tumors, to study the effect of the immune system on brain tumor pathogenesis, and to evaluate immunotherapies ( 24 , 38 , 39 ).…”

“…Orthotopic xenografts usually apply tumor cells/or tissues to the location where the original tumor is found in patients. Orthotopic xenografts can better mimic the original tumor pathogenesis, retain histological and molecular characteristics of original tumors as well as tumor host interactions ( 23 , 25 , 38 , 39 ). However, even orthotopic xenografts may not completely maintain the histological characteristics of human tumors.…”