A hypoxia- and telomerase-responsive oncolytic adenovirus expressing secretable trimeric TRAIL triggers tumour-specific apoptosis and promotes viral dispersion in TRAIL-resistant glioblastoma

Eonju Oh,Jinwoo Hong,Oh-Joon Kwon,Chae-Ok Yun

doi:10.1038/s41598-018-19300-6

Abstract

Glioblastoma is a highly aggressive and malignant type of cancer that is apoptosis resistant and difficult to cure by conventional cancer therapies. In this regard, an oncolytic adenovirus that selectively targets the tumour tissue and induces tumour cell lysis is a promising treatment option. We designed and constructed a hypoxia-responsive and cancer-specific modified human telomerase reverse transcriptase (H5CmTERT) promoter to drive replication of an oncolytic adenovirus (H5CmTERT-Ad). To enhance the anti-tumour efficacy of H5CmTERT-Ad against malignant glioblastoma, we also generated an H5CmTERT-Ad expressing secretable trimeric tumour necrosis factor-related apoptosis-inducing ligand (H5CmTERT-Ad/TRAIL). H5CmTERT promoter-regulated oncolytic adenoviruses showed cancer-specific and superior cell-killing effect in contrast to a cognate control oncolytic adenovirus replicating under the control of the endogenous adenovirus promoter. The cancer cell-killing effects of H5CmTERT-Ad and H5CmTERT-Ad/TRAIL were markedly higher during hypoxia than normoxia owing to hypoxia responsiveness of the promoter. H5CmTERT-Ad/TRAIL showed more potent anti-tumour efficacy than H5CmTERT-Ad did in a xenograft model of TRAIL-resistant subcutaneous and orthotopic glioblastoma through superior induction of apoptosis and more extensive virus distribution in the tumour tissue. Altogether, our findings show that H5CmTERT-Ad/TRAIL can promote dispersion of an oncolytic adenovirus through robust induction of apoptosis in a highly TRAIL-resistant glioblastoma.

Highlights

Glioblastoma is the most aggressive, invasive, and common form of human glioma
We previously reported that an oncolytic adenovirus replicating under the control of mTERT containing an additional c-Myc-binding site and Sp1 sites has a potent and cancer-specific anti-tumour effect that is superior to that mediated by a wild-type human telomerase reverse transcriptase (hTERT) promoter-driven oncolytic adenovirus[18]
To further assess the potent cancer cell killing mediated by H5CmTERT-Ad/TRAIL, we examined the morphology of U87MG glioblastoma cells treated with oncolytic adenoviruses by transmission electron microscopy

Summary

Introduction

Glioblastoma is the most aggressive, invasive, and common form of human glioma. Despite decades of intensive research and advances in conventional anti-cancer modalities, patients with glioblastoma have the mean life expectancy of only 14.6 months[1,2]. Prostate-specific antigen (PSA)-, α-fetoprotein (AFP)-, carcinoembryonic antigen (CEA)-, or other cancer type-specific promoters induce efficient therapeutic gene expression in a cancer cell-specific manner[9,10,11,12]. A modified hTERT promoter containing additional c-Myc- and Sp1-binding sites (mTERT) has been shown to induce stronger transcriptional activity than wild-type hTERT promoter can in tumour cells[18], revealing that oncolytic adenoviruses replicating under the control of the mTERT promoter are good candidates for the treatment of cancers from various tissues of origin. We generated a stTRAIL-expressing oncolytic adenovirus replicating under the control of a hypoxia-responsive and cancer-specific H5CmTERT promoter (H5CmTERT-Ad/TRAIL) to achieve robust and selective cancer cell-killing effect for the treatment of glioblastoma. H5CmTERT-Ad/TRAIL is a promising therapeutic option for the treatment of aggressive glioma

Methods

Results

Conclusion