Browse
Submit Data
Databases
API
Help

Dataset Information

39 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Patient-derived glioblastoma cultures as a tool for small-molecule drug discovery.

ABSTRACT: There is a compelling need for new therapeutic strategies for glioblastoma multiforme (GBM). Preclinical target and therapeutic discovery for GBMs is primarily conducted using cell lines grown in serum-containing media, such as U-87 MG, which do not reflect the gene expression profiles of tumors found in GBM patients. To address this lack of representative models, we sought to develop a panel of patient-derived GBM models and characterize their genomic features, using RNA sequencing (RNA-seq) and growth characteristics, both when grown as neurospheres in culture, and grown orthotopically as xenografts in mice. When we compared these with commonly used GBM cell lines in the Cancer Cell Line Encyclopedia (CCLE), we found these patient-derived models to have greater diversity in gene expression and to better correspond to GBMs directly sequenced from patient tumor samples. We also evaluated the potential of these models for targeted therapy, by using the genomic characterization to identify small molecules that inhibit the growth of distinct subsets of GBMs, paving the way for precision medicines for GBM.

SUBMITTER: Ye LF

PROVIDER: S-EPMC6996910 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Patient-derived lymphoblastoid cell lines harboring mitochondrial DNA mutations as tool for small molecule drug discovery.

Project description:Mitochondrial diseases are a group of devastating disorders for which there is no transformative cure. The majority of therapies for mitochondrial disease-approved, previously tested, or currently in development-are small molecules. The implementation of better cell-based models of mitochondrial disease can accelerate and improve the accuracy of small molecule drug discovery. The objective of this study is to evaluate the use of patient-derived lymphoblastoid cell lines for small molecule research in mitochondrial disease.Five lymphoblastoid cell lines derived from mitochondrial disease patients harboring point mutations in mtND1, mtND4, or mtATP6 were characterized in two high throughput assays assessing mitochondrial function. In a pilot "clinical trial in a dish" experiment, the efficacy of idebenone-an approved therapy for mitochondrial disease-on the lymphoblastoid cell lines was tested. Idebenone increased the basal respiration of all lymphoblastoid cell lines except those harboring the 8993T>G point mutation in mtATP6. Our results posit lymphoblastoid cell lines as a strong model for mitochondrial disease research with small molecules and have implications for the clinical efficacy of idebenone.

| S-EPMC5870301 | biostudies-literature

Comparative analysis of glioblastoma initiating cells and patient-matched EPSC-derived neural stem cells as a discovery tool and drug matching strategy

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-09-17 | GSE155994 | GEO

Comparative analysis of glioblastoma initiating cells and patient-matched EPSC-derived neural stem cells as a discovery tool and drug matching strategy [array]

Project description:Malignant gliomas are the most common intrinsic brain tumors in adults and are associated with a very poor prognosis, which has not improved in the last 20 years. We show here that glioblastoma initiating cells (GIC) and syngeneic neural stem cells derived from enhanced pluripotent stem cells (iNSC) are a suitable novel pre-clinical pipeline to discover new patient-specific disease mechanisms and to identify druggable targets for personalized therapy.

2021-09-17 | GSE155985 | GEO

Comparative analysis of glioblastoma initiating cells and patient-matched EPSC-derived neural stem cells as a discovery tool and drug matching strategy [Seq]

Project description:Malignant gliomas are the most common intrinsic brain tumours in adults and are associated with a very poor prognosis, which has not improved in the last 20 years. We show here that glioblastoma initiating cells (GIC) and syngeneic neural stem cells derived from enhanced pluripotent stem cells (iNSC) are a suitable novel pre-clinical pipeline to discover new patient-specific disease mechanisms and to identify druggable targets for personalised therapy.

2021-09-17 | GSE154367 | GEO

Comparative analysis of glioblastoma initiating cells and patient-matched EPSC-derived neural stem cells as a discovery tool and drug matching strategy [RNA-Seq]

2021-09-17 | GSE154958 | GEO

Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells.

Project description:Transition metals are essential, but deregulation of their metabolism causes toxicity. Here, we report that the compound NSC319726 binds copper to induce oxidative stress and arrest glioblastoma-patient-derived cells at picomolar concentrations. Pharmacogenomic analysis suggested that NSC319726 and 65 other structural analogs exhibit lethality through metal binding. Although NSC319726 has been reported to function as a zinc ionophore, we report here that this compound binds to copper to arrest cell growth. We generated and validated pharmacogenomic predictions: copper toxicity was substantially inhibited by hypoxia, through an hypoxia-inducible-factor-1α-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of deoxyribosyl purines, resulting in cell-cycle arrest. These results suggest that metal-induced DNA damage may be a consequence of exposure to some xenobiotics, therapeutic agents, as well as other causes of copper dysregulation, and reveal a potent mechanism for targeting glioblastomas.

| S-EPMC5959763 | biostudies-literature

Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis.

Project description:Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.

| S-EPMC8230685 | biostudies-literature

Shape shifting leads to small-molecule allosteric drug discovery.

Project description:Enzymes that regulate their activity by modulating an equilibrium of alternate, nonadditive, functionally distinct oligomeric assemblies (morpheeins) constitute a recently described mode of allostery. The oligomeric equilibrium for porphobilinogen synthase (PBGS) consists of high-activity octamers, low-activity hexamers, and two dimer conformations. A phylogenetically diverse allosteric site specific to hexamers is proposed as an inhibitor binding site. Inhibitor binding is predicted to draw the oligomeric equilibrium toward the low-activity hexamer. In silico docking enriched a selection from a small-molecule library for compounds predicted to bind to this allosteric site. In vitro testing of selected compounds identified one compound whose inhibition mechanism is species-specific conversion of PBGS octamers to hexamers. We propose that this strategy for inhibitor discovery can be applied to other proteins that use the morpheein model for allosteric regulation.

| S-EPMC2703447 | biostudies-literature

Evaluation of Small Molecule Drug Uptake in Patient-Derived Prostate Cancer Explants by Mass Spectrometry.

Project description:Patient-derived explant (PDE) culture of solid tumors is increasingly being applied to preclinical evaluation of novel therapeutics and for biomarker discovery. In this technique, treatments are added to culture medium and penetrate the tissue via a gelatin sponge scaffold. However, the penetration profile and final concentrations of small molecule drugs achieved have not been determined to date. Here, we determined the extent of absorption of the clinical androgen receptor antagonist, enzalutamide, into prostate PDEs, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and matrix-assisted laser/desorption ionisation (MALDI) mass spectrometry imaging (MSI). In a cohort of 11 PDE tissues from eight individual patients, LC-MS/MS quantification of PDE homogenates confirmed enzalutamide (10?µM) uptake by all PDEs, which reached maximal average tissue concentration of 0.24-0.50?ng/µg protein after 48?h culture. Time dependent uptake of enzalutamide (50?µM) in PDEs was visualized using MALDI MSI over 24-48?h, with complete penetration throughout tissues evident by 6?h of culture. Drug signal intensity was not homogeneous throughout the tissues but had areas of markedly high signal that corresponded to drug target (androgen receptor)-rich epithelial regions of tissue. In conclusion, application of MS-based drug quantification and visualization in PDEs, and potentially other 3-dimensional model systems, can provide a more robust basis for experimental study design and interpretation of pharmacodynamic data.

| S-EPMC6802206 | biostudies-literature

Discovery of Small-Molecule Inhibitors of the HSP90-Calcineurin-NFAT Pathway against Glioblastoma.

Project description:Glioblastoma (GBM) is among the most common and malignant types of primary brain tumors in adults, with a dismal prognosis. Although alkylating agents such as temozolomide are widely applied as the first-line treatment for GBM, they often cause chemoresistance and remain ineffective with recurrent GBM. Alternative therapeutics against GBM are urgently needed in the clinic. We report herein the discovery of a class of inhibitors (YZ129 and its derivatives) of the calcineurin-NFAT pathway that exhibited potent anti-tumor activity against GBM. YZ129-induced GBM cell-cycle arrest at the G2/M phase promoted apoptosis and inhibited tumor cell proliferation and migration. At the molecular level, YZ129 directly engaged HSP90 to antagonize its chaperoning effect on calcineurin to abrogate NFAT nuclear translocation, and also suppressed other proto-oncogenic pathways including hypoxia, glycolysis, and the PI3K/AKT/mTOR signaling axis. Our data highlight the potential for targeting the cancer-promoting HSP90 chaperone network to treat GBM.

| S-EPMC6430684 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data