Organoid Models of Glioblastoma and Their Role in Drug Discovery

Abstract

Glioblastoma (GBM) is a devastating adult brain cancer with high rates of recurrence and treatment resistance. Cellular heterogeneity and extensive invasion of surrounding brain tissues are characteristic features of GBM that contribute to its intractability. Current GBM model systems do not recapitulate some of the complex features of GBM and have not produced sufficiently-effective treatments. This has cast doubt on the effectiveness of current GBM models and drug discovery paradigms. In search of alternative pre-clinical GBM models, various 3D organoid-based GBM model systems have been developed using human cells. The scalability of these systems and potential to more accurately model characteristic features of GBM, provide promising new avenues for pre-clinical GBM research and drug discovery efforts. Here, we review the current suite of organoid-GBM models, their individual strengths and weaknesses, and discuss their future applications with an emphasis on compound screening.

Perspective: Extending the Utility of Three-Dimensional Organoids by Tissue Clearing Technologies

“…Recently, Lukonin et al (2020) devised an imagingbased drug screening assay of approximately 450,000 intestinal organoids by extracting several features from the image (e.g., signal intensities of marker proteins, area, and circularity of the reaggregates) and clustering the organoids into 15 groups related to seven major phenotypes affected by the screened drugs. Tissue clearing techniques are beginning to be incorporated into such large-scale automated procedures for organoid screening (Silva Santisteban et al, 2017;Boutin et al, 2018b;Grenier et al, 2020;Renner et al, 2020;Rybin et al, 2021), which have been useful for the collection of comprehensive information across organoids and to improve screening accuracy. Histo-cytometry or proteomic imaging by multiplex and multi-modal labeling together with clearing can scale the amount of information (Murray et al, 2015;Li et al, 2017;Park et al, 2018).…”

Human mini brains and spinal cords in a dish: Modeling strategies, current challenges, and prospective advances

“… 88 – 94 Brain tumor organoids were used as models to test novel immunotherapies and to screen small compounds in treating some infamous brain cancers, such as glioblastoma. 95 – 97 Note that several premature spinal organoid models were also developed to model motor neuron diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. 98 Interestingly, human spinal cord organoids containing dorsal spinal cord interneurons and sensory neurons have been placed on multiple-electrode array chips to monitor electrophysiological activity in response to nociceptive modulators as a means to further understand nociceptive circuitry in the context of pain therapy.…”

Glioblastoma organoid technology: an emerging preclinical models for drug discovery

“…Jacob et al [54] later improved on this model, coining the term "GBOs" to represent these GBM organoids [62]. GBOs were generated without mechanical or enzymatic dissociation of patient-derived samples into single cells.…”