TRAIL gene therapy: from preclinical development to clinical application

Abstract

Numerous studies have investigated the potential use of TNF-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic since its discovery in 1995--because TRAIL is a potent inducer of apoptosis in tumor cells but not in normal cells and tissues. Consequently, a great deal is known about TRAIL/TRAIL receptor expression, the molecular components of TRAIL receptor signaling, and methods of altering tumor cell sensitivity to TRAIL-induced apoptosis. Our laboratory was the first to report the possibility of TRAIL gene transfer therapy as an alternative method of using TRAIL as an antitumor therapy. As with recombinant proteins administered systemically, intratumoral TRAIL gene delivery also has limitations that can restrict its full potential. Translating the preclinical TRAIL studies into the clinic has started, with the hope that TRAIL will exhibit robust tumoricidal activity against human primary tumors in situ with minimal toxic side effects.

Figure 1

Schematic representation of TRAIL receptor signaling.

Figure 2

HDACi treatment increases prostate tumor cell sensitivity to adenovirus infection and Ad5-TRAIL-induced cell death. DU-145 cells were treated for 16 h with vehicle or suberoylanilide hydroxamic acid (SAHA) at the indicated concentrations. A The cells were then cultured with (A) Ad5-eGFP (100 pfu/cell) or (B) Ad5-TRAIL (at the indicated doses) for 24 h. Cell infection was determined by quantitiating the percentage of GFP+ cells by flow cytometry. Cell death was determined by crystal violet staining.