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TRAIL stabilization and cancer cell sensitization to its pro-apoptotic activity achieved through genetic fusion with

Elena Brin1, Katherine Wu1, Eleanor Dagostino1

  • 1Polaris Pharmaceuticals, San Diego, CA, USA.

Oncotarget
|January 18, 2019
PubMed

Insights

A novel fusion protein combining Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) with arginine deiminase (ADI) demonstrates enhanced anti-cancer efficacy. This ADI-TRAIL fusion protein overcomes limitations of TRAIL alone, showing superior tumor regression in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces cancer cell apoptosis but faces clinical limitations due to poor pharmacokinetics and resistance.
  • Recombinant TRAIL shows preclinical promise, yet clinical translation is hindered by suboptimal in vivo behavior and acquired resistance mechanisms.

Purpose of the Study:

  • To develop and evaluate a novel fusion protein combining TRAIL with arginine deiminase (ADI) to enhance anti-cancer efficacy and overcome TRAIL resistance.
  • To investigate the synergistic effects and in vivo performance of the ADI-TRAIL fusion protein in preclinical cancer models.

Main Methods:

  • Construction and characterization of an ADI-TRAIL fusion protein.
  • Assessment of fusion protein efficacy in various cancer cell lines and combination studies with standard-of-care drugs.
  • Evaluation of ADI-TRAIL fusion protein's pharmacokinetics, tumor localization, and anti-tumor activity in HCT116 xenograft models.

Main Results:

  • The ADI-TRAIL fusion protein exhibited synergistic effects, downregulating survivin and upregulating DR5 receptor expression, thereby sensitizing cancer cells to apoptosis.
  • The fusion protein demonstrated significant efficacy across multiple cell lines and synergized with certain standard chemotherapeutic agents.
  • In HCT116 xenografts, ADI-TRAIL localized to tumors and induced dose-dependent regression, outperforming recombinant TRAIL at equivalent molar concentrations.

Conclusions:

  • The ADI-TRAIL fusion protein represents a promising therapeutic strategy by combining the apoptotic effects of TRAIL with the sensitizing properties of ADI.
  • This novel fusion protein overcomes key limitations of TRAIL, offering improved pharmacokinetics and enhanced anti-tumor activity.
  • ADI-TRAIL warrants further investigation as a potential next-generation cancer therapeutic agent.
Keywords:
TRAILanti-cancer biologicapoptosisarginine deiminasefusion protein

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