Journal of Genetic Syndromes & Gene Therapy
Open Access

Cancer therapy adenoviruses which are selectively activated by hypoxia-inducible factor (HIF)

International Conference on Genetic Syndromes & Gene Therapy

November 19-21, 2012 Hilton San Antonio Airport, USA

Dawn E. Post

Scientific Tracks Abstracts: J Genet Syndr Gene Ther

Abstract :

Hypoxia-inducible factor (HIF) is a key target for anti-tumor therapy. First, HIF is expressed in a wide range of primary tumors, metastases, and cancer stem cells whereas HIF is undetectable in normal healthy tissues. Second, HIF has a critical role in promoting tumor cell survival, tumor growth, angiogenesis and invasion/metastasis. To eradicate HIF-active tumor, we created a second-generation oncolytic adenovirus that is selectively activated by HIF (HIF-Ad). For this, we inserted a novel bi-directional HIF-responsive promoter into the Ad genome. The right arm of the promoter regulates expression of E1A, a gene which is required for Ad replication. Treatment of human tumor cells in culture with HIF-Ad leads to robust E1A expression, virus replication, and tumor cell death under hypoxic/HIF-active conditions. Treatment of subcutaneous human tumor xenografts in mice with HIF-Ad results in high levels of intratumoral virus replication and a decrease in both intratumoral HIF-activity and tumor growth. A major advantage of HIF-Ad is that transgenes can be easily inserted into the viral genome without deleting important viral genes. For this, we use the left arm of the bi-directional HIF-responsive promoter. Using this approach, we created a modified HIF-Ad which expresses the multimodal anti-tumorigenic interleukin-4 (IL4) cytokine. HIF- Ad-IL4 treatment leads to regressions in tumor size by 70%. In addition, the anti-tumor efficacy of HIF-Ad-IL4 is up to 6-fold greater than HIF-Ad treatment. Our data demonstrates that we have developed a potent and efficacious HIF-activated oncolytic Ad for cancer treatment.

Biography :

Dawn Post completed her Ph.D. from George Washington University, Washington D.C. in 1995 and postdoctoral studies from the University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC and Emory University Winship Cancer Institute, Atlanta, GA. Dr. Post is currently Director of the Neuro-Oncology Laboratory at SUNY Upstate Medical University. She has published more than 20 research papers, review articles, and book chapters. In addition, Dr. Post has 14 years of research experience with developing and testing oncolytic viruses for cancer therapy.