Hypoxia Targeted Infectious Knockdown for the Treatment of Solid Tumors
2Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Israel
Introduction
Intratumoral hypoxia characterizes solid tumors. Tumor cells in hypoxic regions are resistant to chemotherapy and radiation. We have previously shown that knockdown of either CREB or HIF-1 inhibits tumor progression. Currently, there are no effective treatments for metastatic uveal melanoma (UM). The aim of this study is to test the effect of infectious KD of CREB and HIF-1 on UM.
Methods
UM cells expressing luciferase and infected with a MuLV-based replication-competent retroviral (RCR) vector expressing shRNA targeting either CREB or HIF-1 were tested for knockdown efficiency in vitro. The effect of these armed viruses on subcutaneous tumor growth in mice was monitored weekly via bioluminescence (IVIS). 5 weeks post-implantation, tumors were excised and analyzed.
Results
Infection with the armed viruses resulted in an efficient knockdown of CREB, HIF-1, and downstream genes. The efficient knockdown resulted in an inhibition of cell growth in vitro. Subcutaneous xenografts infected with armed viruses had a halted growth rate as opposed to the steady fast growth of the control tumors. In correlation with the non-invasive luciferase-based method, at the end of the experiment, the mean weight of HIF-1-knockdown- and CREB-knockdown-tumors was only 42% and 16%, respectively, of the mean tumor weight of the control tumors.
Conclusion
Infectious knockdown via armed viruses targeting the hypoxia regulators CREB and HIF-1 is effective against metastatic UM in vitro and in vivo. These results indicate that armed viruses controlling the cellular response to hypoxia may be the basis of a new treatment modality for solid tumors.
Powered by Eventact EMS