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A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
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Single-Cell Phosphoproteomics Resolves Adaptive Signaling Dynamics and Informs Targeted Combination Therapy in

Wei Wei1, Young Shik Shin2, Min Xue3

  • 1Division of Chemistry and Chemical Engineering, NanoSystems Biology Cancer Center, California Institute of Technology, Pasadena, CA 91125, USA; Department of Applied Physics and Materials Science, California Institute of Technology, Pasadena, CA 91125, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Cancer Cell
|April 13, 2016
PubMed

Insights

Early detection of glioblastoma (GBM) drug resistance is possible by analyzing protein signaling coordination. This method identified combination therapies for sustained tumor suppression, even with non-obvious drug pairings.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Intratumoral heterogeneity in signaling networks can drive targeted therapy resistance in cancers.
  • Glioblastoma (GBM) is a lethal brain cancer where therapy resistance is a significant challenge.

Purpose of the Study:

  • To investigate early adaptive resistance mechanisms in glioblastoma.
  • To identify novel combination therapies for overcoming treatment resistance.

Main Methods:

  • Single-cell phosphoproteomics was employed on a patient-derived in vivo GBM model.
  • An analytical approach was used to detect changes in protein signaling coordination.

Main Results:

  • Alterations in protein signaling coordination were detected as early as 2.5 days post-treatment.
  • These early changes predicted drug resistance before clinical manifestation.
  • Effective combination therapies were identified, leading to complete and sustained tumor suppression in vivo.

Conclusions:

  • Analyzing signal coordination provides an early indicator of adaptive resistance.
  • This approach can identify actionable targets for combination drug therapy.
  • Non-obvious drug combinations show promise in overcoming glioblastoma resistance.

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