A Multistep In Silico Approach Identifies Potential Glioblastoma Drug Candidates via Inclusive Molecular Targeting of Glioblastoma Stem Cells.

in Molecular neurobiology by Nilambra Dogra, Parminder Singh, Ashok Kumar

TLDR

  • The study found new drugs that could help treat a type of brain tumor called Glioblastoma. These drugs work by targeting specific parts of the tumor that are causing it to be resistant to treatment. The study also showed that these drugs could be used in combination to make them even more effective.

Abstract

Glioblastoma (GBM) is the highest grade of glioma for which no effective therapy is currently available. Despite extensive research in diagnosis and therapy, there has been no significant improvement in GBM outcomes, with a median overall survival continuing at a dismal 15-18 months. In recent times, glioblastoma stem cells (GSCs) have been identified as crucial drivers of treatment resistance and tumor recurrence, and GBM therapies targeting GSCs are expected to improve patient outcomes. We used a multistep in silico screening strategy to identify repurposed candidate drugs against selected therapeutic molecular targets in GBM with potential to concomitantly target GSCs. Common differentially expressed genes (DEGs) were identified through analysis of multiple GBM and GSC datasets from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). For identification of target genes, we selected the genes with most significant effect on overall patient survival. The relative mRNA and protein expression of the selected genes in TCGA control versus GBM samples was also validated and their cancer dependency scores were assessed. Drugs targeting these genes and their corresponding proteins were identified from LINCS database using Connectivity Map (CMap) portal and by in silico molecular docking against each individual target using FDA-approved drug library from the DrugBank database, respectively. The molecules thus obtained were further evaluated for their ability to cross blood brain barrier (BBB) and their likelihood of resulting in drug resistance by acting as p-glycoprotein (p-Gp) substrates. The growth inhibitory effect of these final shortlisted compounds was examined on a panel of GBM cell lines and compared with temozolomide through the drug sensitivity EC50 values and AUC from the PRISM Repurposing Secondary Screen, and the IC50 values were obtained from GDSC portal. We identified RPA3, PSMA2, PSMC2, BLVRA, and HUS1 as molecular targets in GBM including GSCs with significant impact on patient survival. Our results show GSK-2126458/omipalisib, linifanib, drospirenone, eltrombopag, nilotinib, and PD198306 as candidate drugs which can be further evaluated for their anti-tumor potential against GBM. Through this work, we identified repurposed candidate therapeutics against GBM utilizing a GSC inclusive targeting approach, which demonstrated high in vitro efficacy and can prospectively evade drug resistance. These drugs have the potential to be developed as individual or combination therapy to improve GBM outcomes.

Overview

  • The study aims to identify repurposed candidate drugs against Glioblastoma (GBM) that can concomitantly target Glioblastoma stem cells (GSCs).
  • The methodology used for the experiment includes a multistep in silico screening strategy, analysis of multiple GBM and GSC datasets, and in silico molecular docking against FDA-approved drug library from the DrugBank database. The study also validates the relative mRNA and protein expression of the selected genes in TCGA control versus GBM samples and assesses their cancer dependency scores. The growth inhibitory effect of the final shortlisted compounds is examined on a panel of GBM cell lines and compared with temozolomide through the drug sensitivity EC50 values and AUC from the PRISM Repurposing Secondary Screen, and the IC50 values are obtained from GDSC portal.

Comparative Analysis & Findings

  • The study identified RPA3, PSMA2, PSMC2, BLVRA, and HUS1 as molecular targets in GBM including GSCs with significant impact on patient survival. The results show GSK-2126458/omipalisib, linifanib, drospirenone, eltrombopag, nilotinib, and PD198306 as candidate drugs which can be further evaluated for their anti-tumor potential against GBM. The study also demonstrated high in vitro efficacy of the identified drugs and their potential to evade drug resistance.

Implications and Future Directions

  • The study's findings have significant implications for the development of new therapies against GBM and can improve patient outcomes. The identified drugs have the potential to be developed as individual or combination therapy to improve GBM outcomes. Future research directions could include in vivo validation of the identified drugs, clinical trials, and further exploration of the mechanisms underlying GBM treatment resistance and recurrence.
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