Oncolytic Adenoviruses, Cancer Stem Cells, Autophagy
Hong “Helen” Jiang, Ph.D.
My research focuses on understanding the interactions of adenoviral and cellular proteins to develop novel therapies for malignant gliomas. Collaborating with Dr. Fueyo, we constructed and showed the antiglioma effect of Delta-24-RGD, an adenovirus that selectively infects and replicates in tumor cells. Delta-24-RGD has proved to be highly effective against tumors in animal experiments, and is currently awaiting clinical trials.
The combination of oncolytic vectors such as Delta-24-RGD with chemotherapy represents a promising line of treatment for gliomas. Everolimus (RAD001) is an orally available derivative of rapamycin, and has been shown, in several pre-clinical studies, to have a potent anticancer effect with negligible toxicity. We showed that treatment of glioma cells with a combination of Delta-24-RGD and RAD001 produced a synergistic effect in the laboratory. In animal studies, the use of Delta-24-RGD/RAD001significantly increased the median survival and yielded a long-term survival rate of 80%
Because adenoviral proteins can completely overcome the molecular machinery of the infected cell, we hypothesized that Delta-24-RGD may act as a potent therapeutic agent to target brain tumor stem cells and prevent them from developing resistance to other forms of therapy. Our study was the first to report that brain tumor stem cells are susceptible to adenovirus-mediated cell death via autophagy in laboratory and animal experiments. We expect that a better understanding of autopahgy will provide us with new tools to improve the therapy of gliomas.
Alonso MM, Jiang H, Yokoyama T, Xu J, Bekele NB, Lang FF, Kondo S, Gomez-Manzano C, Fueyo J. Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death. Mol Ther. 2008 Mar;16(3):487-93.
Jiang H, Gomez-Manzano C, Aoki H, Alonso MM, Kondo S, McCormick F, Xu J, Kondo Y, Bekele BN, Colman H, Lang FF, Fueyo J. Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death. J Natl Cancer Inst. 2007 Sep 19;99(18):1410-4.
Alonso MM, Cascallo M, Gomez-Manzano C, Jiang H, Bekele BN, Perez-Gimenez A, Lang FF, Piao Y, Alemany R, Fueyo J. ICOVIR-5 shows E2F1 addiction and potent antiglioma effect in vivo. Cancer Res. 2007 Sep 1;67(17):8255-63.
Lee OH, Xu J, Fueyo J, Alonso MM, Liu D, Martin V, Jiang H, Piao Y, Liu TJ, Gomez-Manzano C. Angiopoietin-2 decreases vascular endothelial growth factor expression by modulating HIF-1 alpha levels in gliomas. Oncogene. 2008 Feb 21;27(9):1310-4.
Alonso MM, Gomez-Manzano C, Jiang H, Bekele NB, Piao Y, Yung WK, Alemany R, Fueyo J. Combination of the oncolytic adenovirus ICOVIR-5 with chemotherapy provides enhanced anti-glioma effect in vivo. Cancer Gene Ther. 2007 Aug;14(8):756-61.
Olson MV, Johnson DG, Jiang H, Xu J, Alonso MM, Aldape KD, Fuller GN, Bekele BN, Yung WKA, Gomez-Manzano C, Fueyo J. Transgenic E2F1 expression in the mouse brain induces a human-like bimodal pattern of tumors. Cancer Res, 2007;67:4005-9.
Jiang H, Olson MV, Medrano DR, Lee OH, Xu J, Piao Y, Alonso MM, Gomez-Manzano C, Hung MC, Yung WK, Fueyo J. Jiang H, Alonso MM, Gomez-Manzano C, Piao Y, Fueyo J. Oncolytic viruses and DNA-repair machinery: overcoming chemoresistance of gliomas. Expert Rev Anticancer Ther. 2006;6:1585-92. .
Jiang H, Olson MV, Medrano DR, Lee OH, Xu J, Piao Y, Alonso MM, Gomez-Manzano C, Hung MC, Yung WK, Fueyo J. A novel CRM1-dependent nuclear export signal in adenoviral E1A protein regulated by phosphorylation. FASEB J. 2006;20:2603-5.