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Targeting multiple pathways in gliomas with stem cell and viral delivered S-TRAIL and Temozolomide

Shawn Hingtgen1, Xianghui Ren, Ernie Terwilliger

  • 1Massachusetts General Hospital, Harvard Medical School, 13th Street, Charlestown, MA 02129, USA.

Molecular Cancer Therapeutics
|November 13, 2008
PubMed

Insights

Novel adeno-associated virus (AAV) delivery of secreted Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) effectively targets gliomas. Combining AAV-TRAIL with temozolomide enhances cancer cell killing, offering a potent new therapeutic strategy.

Area of Science:

  • Oncology
  • Gene Therapy
  • Molecular Biology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits selective tumor cell cytotoxicity but faces clinical limitations due to short half-life and poor delivery.
  • TRAIL resistance in tumor cells further compromises its therapeutic efficacy.
  • Gliomas, particularly glioblastoma, remain challenging to treat, necessitating innovative therapeutic approaches.

Purpose of the Study:

  • To investigate novel adeno-associated virus (AAV) vector-mediated delivery systems for recombinant secreted TRAIL (S-TRAIL) in glioma treatment.
  • To evaluate the efficacy of S-TRAIL delivery in overcoming TRAIL resistance in glioma cell lines.
  • To assess the synergistic potential of combining S-TRAIL therapy with temozolomide in resistant glioma models.

Main Methods:

  • Engineering of AAV vectors encoding S-TRAIL and bioluminescent-fluorescent marker fusion proteins for targeted delivery.
  • In vitro assessment of AAV-S-TRAIL-induced glioma cell killing and caspase-3/7 activation.
  • In vivo evaluation of AAV vector delivery efficiency and tumor progression attenuation using dual bioluminescent imaging.
  • Analysis of temozolomide's effects on cell cycle, checkpoint proteins, and death receptor expression.
  • Combination therapy studies involving AAV-S-TRAIL or neural stem cell-S-TRAIL with temozolomide.

Main Results:

  • AAV-delivered S-TRAIL demonstrated varying degrees of glioma cell killing, correlated with caspase-3/7 activation.
  • In vivo studies confirmed efficient AAV vector delivery to glioma tumors, leading to significant tumor progression attenuation.
  • Temozolomide treatment induced G(2)-M phase arrest, activated Chk1, and upregulated death receptors in glioma cells.
  • Combined S-TRAIL and temozolomide therapy significantly enhanced cell killing and upregulated proapoptotic proteins, particularly in TRAIL-resistant cells.

Conclusions:

  • AAV-mediated delivery of S-TRAIL represents a promising strategy for targeting gliomas.
  • Combination therapy with temozolomide and S-TRAIL exhibits enhanced cytotoxic effects against TRAIL-resistant gliomas.
  • This combined approach holds potential as a novel therapeutic option for glioblastoma patients.

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