Pre-clinical tumor models of primary brain tumors: Challenges and opportunities

Abstract

Primary brain tumors are a heterogeneous group of malignancies that originate in cells of the central nervous system. A variety of models tractable for preclinical studies have been developed to recapitulate human brain tumors, allowing us to understand the underlying pathobiology and explore potential treatments. However, many promising therapeutic strategies identified using preclinical models have shown limited efficacy or failed at the clinical trial stage. The inability to develop therapeutic strategies that significantly improve survival rates in patients highlight the compelling need to revisit the design of currently available animal models and explore the use of new models that allow us to bridge the gap between promising preclinical findings and clinical translation. In this review, we discuss current strategies used to model glioblastoma, the most malignant brain tumor in adults and highlight the shortcomings of specific models that must be circumvented for the development of innovative therapeutic strategies.

Keywords: Brain tumor model; Glioblastoma; Glioma; Neurooncology; Therapeutic development.

Figure 1:. In vivo models of glioblastoma in rodents.

A) Traditional methods include ENU administration in pregnant rodents leading to tumor formation, which can be harvested and processed into cell lines in vitro. B) Genetically engineered systems include reversible systems using Tet regulation (i) or Cre recombinase (ii). C) Patient derived xenografts can be injected subcutaneously or directly into cerebral cortex. D) Resection models designed to recapitulate the tumor environment following primary resection of tumors. (i,ii) Cartoons showing GBM tumors before and after tumor resection in the brain mice. (iii-vii). Mice with established GBM-Fluc-mCherry GBMs were imaged by bioluminescence imaging (iii,iv) and intravital microscopy (v,vi) before and after tumor resection. Kaplan-Meier survival curves of mice with and without resected U87-Fluc-mCherry tumors (vii) (adapted from Kauer et al 2012) (82).

Figure 2:. Alternative models of glioblastoma.

A) The zebrafish model using both embryos and adult species allow modeling of the disease to be performed quickly and can allow tumors to be imaged in real time. B) The drosophila model allows the study of glioblastoma using various genetic manipulations. C) Humanized mouse models allow modeling of tumors with partially humanized immune systems using three methods. (i) hu-PBMC cells are introduced after patient tumor cell engraftment. (ii) hCD34+ stem cells are engrafted before the patient tumor cells are added. (iii) Humanized mouse models can be created through the transplantation of fetal liver and thymus under the kidney capsule. CD34+ cells are engrafted afterwards.