Patient-Derived Glioma Models: From Patients to Dish to Animals

Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults associated with a poor survival. Current standard of care consists of surgical resection followed by radiation and chemotherapy. GBMs are highly heterogeneous, having a complex interaction among different cells within the tumor as well as the tumor microenvironment. One of the main challenges in the neuro-oncology field in general, and GBM in particular, is to find an optimum culture condition that maintains the molecular genotype and phenotype as well as heterogeneity of the original tumor in vitro and in vivo. Established cell lines were shown to be a poor model of the disease, failing to recapitulate the phenotype and harboring non-parental genotypic mutations. Given the growing understanding of GBM biology, the discovery of glioma cancer stem-like cells (GSCs), and their role in tumor formation and therapeutic resistance, scientists are turning more towards patient-derived cells and xenografts as a more representative model. In this review, we will discuss the current state of patient-derived GSCs and their xenografts; and provide an overview of different established models to study GBM biology and to identify novel therapeutics in the pre-clinical phase.

First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma

“…Author Manuscript Published OnlineFirst on January 14, 2020; DOI: 10.1158/1078-0432.CCR- rational GDC-0084 combinations in patient-derived glioblastoma organoid models may be of value (38,39). This agent is being evaluated in a Phase I/II trial in patients with newly-diagnosed glioblastoma with unmethylated DNA-methylguanine-methyltransferase promoter status as adjuvant therapy following surgical resection and initial chemoradiation with temozolomide (NCT03522298), and in Phase II trials in diffuse intrinsic pontine glioma and diffuse midline gliomas (NCT03696355), HER2 positive breast cancer brain metastases (NCT03765983) and brain metastases with PI3K pathway activation (NCT03994796).…”

Low Dose Astaxanthin Treatments Trigger the Hormesis of Human Astroglioma Cells by Up-Regulating the Cyclin-Dependent Kinase and Down-Regulated the Tumor Suppressor Protein P53

“…Previous reports have shown that U251-GM and CRT-MG cells show a similar response to CaCl 2 and H 2 O 2 treatment [ 36 ]; however, other similarities and differences between the two cell lines are yet to be analyzed. From the three astroglioma cell lines studied, our results showed that AXT had a hormetic effect only on U251-MG cells, demonstrating the limitations of in vitro studies for evaluating the effect of anti-cancer drugs in patients [ 37 ]. Nonetheless, this is, to our knowledge, the first report that showed that AXT might have a hormetic effect on cancer cells.…”

Sphere-Forming Culture for Expanding Genetically Distinct Patient-Derived Glioma Stem Cells by Cellular Growth Rate Screening

“…We evaluated the 6-day cell growth rates of 72 GSCs against 132 distinct combinations, using 13 tumor-associated GFs in a 384-well GFSCAN plate. The 13 GFs, including E&F, MDK, PlGF, IL-6, PEDF, SHH, IGF1, TGF-β, neuregulin 1 (NRG-1), hepatocyte growth factor (HGF), PDGF and semaphorin 3A (Sema3A) have been linked to the aggressive phenotypes of gliomas, such as cell proliferation, survival, invasion, cancer stemness and the resistance to standard therapies [14,16,18,27,29,.…”