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Updated: Jan 30, 2026

A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
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An Integrated Stress Response Agent that Modulates DR5-Dependent TRAIL Synergy Reduces Patient-Derived Glioma Stem

Saad Sheikh1, Deeksha Saxena2, Xiaobing Tian3

  • 1Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. JayD@uphs.upenn.edu saad.sheikh@uphs.upenn.edu.

Molecular Cancer Research : MCR
|January 16, 2019
PubMed

Insights

Targeting the integrated stress response (ISR) pathway with NH125 shows promise for glioblastoma recurrence. This compound sensitizes glioma stem cells (GSC) to TRAIL therapy, reducing tumor volume in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Glioblastoma recurrence is common, driven by treatment-resistant glioma stem cells (GSC).
  • GSCs survive therapies like irradiation and temozolomide (TMZ) by activating DNA damage pathways.
  • The integrated stress response (ISR) pathway offers a potential target to overcome treatment resistance.

Purpose of the Study:

  • To identify novel compounds that induce ISR-dependent death receptor 5 (DR5) expression.
  • To evaluate the efficacy of identified compounds in sensitizing GSCs to TRAIL therapy.
  • To assess the therapeutic potential of NH125 in preclinical glioblastoma models.

Main Methods:

  • Development of a cell-based assay to screen for ISR-dependent DR5 inducers.
  • Screening of commercial compound libraries to identify potent DR5 inducers.
  • In vitro and in vivo studies using GSCs, glioblastoma cell lines, and xenografts.

Main Results:

  • NH125 was identified as a potent inducer of DR5 expression via the EIF2α-ATF4-CHOP axis.
  • NH125 significantly reduced GSC viability and synergized with TRAIL at lower doses.
  • Encapsulated NH125 in PEG-PCL nanoparticles decreased glioblastoma xenograft tumor volume.

Conclusions:

  • Modulating the ISR pathway is a promising strategy to target treatment-refractory GSCs.
  • NH125 demonstrates potential as a therapeutic agent for glioblastoma by targeting GSCs.
  • NH125 combined with TRAIL offers a synergistic approach to combat glioblastoma recurrence.

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