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A dual PI3K/mTOR inhibitor, PI-103, cooperates with stem cell-delivered TRAIL in experimental glioma models

Tugba Bagci-Onder1, Hiroaki Wakimoto, Maarten Anderegg

  • 1Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Cancer Research
|November 19, 2010
PubMed

Insights

This study shows PI-103, a PI3-kinase/mTOR inhibitor, effectively reduces glioma growth and invasion. Combining PI-103 with stem cell-delivered S-TRAIL significantly enhances antitumor effects in preclinical models.

Area of Science:

  • Neuro-oncology
  • Molecular targeted therapy
  • Cancer stem cell research

Background:

  • Glioma resistance to therapies and invasiveness hinder treatment success.
  • Targeting PI3-kinase/mTOR pathway is a potential therapeutic strategy for gliomas.
  • Stem cell-based delivery of therapeutic agents offers novel treatment approaches.

Purpose of the Study:

  • To evaluate the efficacy of PI-103, a PI3-kinase/mTOR inhibitor, against glioma.
  • To investigate the combined therapeutic potential of PI-103 and stem cell-delivered secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL).
  • To assess the effects in established glioma cell lines, primary glioma-initiating cells, and orthotopic mouse models.

Main Methods:

  • In vitro and in vivo experiments using glioma cell lines and primary cells.
  • Orthotopic mouse models of glioma.
  • Coculture systems with neural stem cells (NSC) and glioma cells.
  • Bimodal optical imaging for tumor volume assessment.
  • Systemic administration of PI-103 and NSC-derived S-TRAIL.

Main Results:

  • PI-103 inhibited glioma cell proliferation and invasion, inducing G(0)-G(1) cell cycle arrest.
  • PI-103 demonstrated significant attenuation of orthotopic tumor growth in vivo.
  • Combination therapy of PI-103 with NSC-delivered S-TRAIL resulted in a significant reduction in glioma tumor volumes.
  • PI-103 augmented the response of glioma cells to S-TRAIL in coculture models.

Conclusions:

  • PI-103 exhibits significant antitumor effects against intracranial gliomas, including inhibition of proliferation and invasion.
  • Combining PI-103 with stem cell-delivered S-TRAIL offers a potent therapeutic strategy for malignant gliomas.
  • These findings provide a preclinical basis for utilizing systemically delivered antiproliferative agents and stem cell-based proapoptotic therapies in glioma treatment.

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