A hypoxia-selective oncolytic adenovirus for cancer therapy

Abstract

Purpose/Objective: The goal for this study is to develop a novel adenovirus gene therapy vector that can selectively replicate in and subsequently lyse hypoxic tumor cells, which are usually more resistant to radiation and a major stimulator of tumor angiogenesis. Materials/Methods: Our strategy is based on the understanding that the Hif1a transcription factor is the most important molecular factor that appears to be universally activated in hypoxic tumor cells. We attempted to exploit this unique feature of hypoxic tumor cells to design conditionally replicative adenovirus vectors that will target hypoxic regions of tumors. The approach we have taken is to engineer adenovirus vectors with their E1 genes, which are essential for virus replication, under the control of hypoxia-activated promoter. This promoter is an artificial promoter that can be activated hundreds of fold when tumor cells are subject to hypoxia. It is based on the Hif1a-binding sequence in the vascular endothelial growth factor gene (VEGF). Results: -We have successfully engineered a series of vectors that encode various reporter and therapeutic genes. -Our data in tissue culture indicate that these vectors can indeed replicate and lyse hypoxic tumor cells with a differentiation factor of at least 100:1 in hypoxic vs normoxic tumor cells. -We have also obtained data that demonstrate significant hypoxia-specific replication and anti-tumor efficacy in vivo. Both virus infection and gene expression efficiency of the hypoxia-selective virus vector are several hundred fold higher compared to conventional non-replicative virus vectors. -Preliminary data indicate that our vectors had significant anti-tumor efficacy either alone or in combination with radiotherapy. Conclusions: Our hypoxia-selective oncolytic adenovirus gene therapy approach is a promising way to target hypoxic tumor cells. It may provide significantly anti-tumor benefits when combined with ionizing radiation.