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A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
A sub-pathway based method to identify candidate drugs for glioblastomas
Yong-ri Zheng1, Kai Kang, Jian-jiao Wang
1Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Bao Jian Road 148, Harbin, 150081, People's Republic of China.
Abstract:
Glioblastomas (GBM) are the most common primary malignant brain tumors with a high invasiveness and resistance to radiation and other treatments. The need for the development of new therapeutic agents for GBM is urgent. Here, we aimed to explore the metabolic mechanism of GBM and identified potential novel drugs for GBM by a sub-pathway-based method. By using the GBM microarray data from "The Cancer Genome Atlas" database, we first identified the 274 differentially expressed genes between GBM and normal samples. Then, we identified 18 significant enriched metabolic sub-pathways that may involve in the development of GBM. Finally, by an integrated analysis of GBM-involved sub-pathways and drug-affected sub-pathways, we identified 66 novel small-molecular drugs capable to target the GBM-involved sub-pathways. Our method could not only identify existing drug (paclitaxel) for GBM, but also predict potentially novel agents (pergolide) that might have therapeutic effects. We also experimentally verified that pergolide could induce GBM cell death. These candidate small-molecular drugs identified by our approach may provide insights into a novel therapy approach for GBM.
Insights
New drugs targeting glioblastoma (GBM) metabolic pathways are urgently needed. This study identified 66 potential small-molecule drugs, including pergolide, that show promise for treating this aggressive brain cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glioblastomas (GBM) are aggressive primary brain tumors known for invasiveness and treatment resistance.
- There is a critical need for novel therapeutic strategies to improve GBM patient outcomes.
Purpose of the Study:
- To investigate the metabolic mechanisms underlying GBM development.
- To identify novel small-molecule drugs targeting GBM-specific metabolic sub-pathways.
Main Methods:
- Differential gene expression analysis of GBM versus normal samples using The Cancer Genome Atlas (TCGA) data.
- Identification of significantly enriched metabolic sub-pathways in GBM.
- Integration of GBM-involved sub-pathways with drug-affected sub-pathways to predict novel therapeutic agents.
Main Results:
- Identified 274 differentially expressed genes and 18 significant metabolic sub-pathways in GBM.
- Discovered 66 potential small-molecule drugs targeting GBM metabolic pathways.
- Validated pergolide's ability to induce GBM cell death, suggesting its therapeutic potential.
Conclusions:
- A sub-pathway-based drug discovery approach can identify novel therapeutic candidates for glioblastoma.
- Pergolide emerges as a promising novel agent for GBM treatment.
- The identified drugs offer new avenues for glioblastoma therapy development.
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