Cancer gene therapy using a novel secretable trimeric TRAIL

Area of Science:

• Molecular Biology
• Cancer Gene Therapy
• Virology

Background:

• Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces cancer cell apoptosis without harming normal cells.
• Previous work created a gene for secretable, trimeric TRAIL (stTRAIL) with potent apoptotic activity.
• TRAIL protein has rapid blood clearance issues when administered systemically.

Purpose of the Study:

• To develop an adenoviral vector (Ad-stTRAIL) delivering the stTRAIL gene for cancer gene therapy.
• To evaluate the efficacy and safety of Ad-stTRAIL in preclinical cancer models.

Main Methods:

• Constructed an adenoviral vector (Ad-stTRAIL) encoding secretable trimeric TRAIL (stTRAIL).
• Tested Ad-stTRAIL's apoptosis-inducing capacity in various cancer cell lines (HeLa, MDA-MB-231, A549, HCT116, U-87MG) in vitro.
• Assessed tumor growth suppression and safety in a human glioma (U-87MG) xenograft model in vivo.
• Compared Ad-stTRAIL efficacy with Ad-flTRAIL (full-length TRAIL) in a mixed-cell tumor model.

Main Results:

• Ad-stTRAIL potently induced apoptosis in multiple cancer cell lines in vitro.
• Intratumoral Ad-stTRAIL delivery significantly suppressed U-87MG glioma growth in vivo with no adverse effects.
• Expressed stTRAIL persisted in tumor tissues for over 4 days.
• Ad-stTRAIL demonstrated superior tumor suppressor activity compared to Ad-flTRAIL.

Conclusions:

• Adenoviral vector-mediated delivery of secretable trimeric TRAIL (Ad-stTRAIL) is a potent strategy for cancer gene therapy.
• Ad-stTRAIL effectively induces apoptosis and suppresses tumor growth, particularly in glioma models.
• This approach offers a promising therapeutic potential for various human cancers.