Replication-Competent Oncolytic Adenoviruses, Tumor Cell Cycle Control
Juan Fueyo, M.D.
The research of my laboratory aims to develop effective brain tumor treatments using oncolytic adenoviruses. Oncolytic viruses are designed to selectively infect tumor cells. Each infected tumor cell produces 10,000 more viruses that can seek out other tumor cells. Because a common genetic defect in tumor cells is inactivation of the retinoblastoma (Rb) tumor suppressor, we have constructed an adenovirus (Delta24) that selectively infects cells with inactive Rb. Thus the virus selectively infects and multiplies in tumor cells, generating more copies of the virus to infect and kill more tumor cells. Encouraged by Delta24 pre-clinical data, we have planned a phase I clinical trial to begin in 2008. We have received a favorable NCI-sponsored toxicology report for Delta24, and currently we are preparing the Investigational New Drug (IND) documentation for the FDA. Moreover, based on the Delta24 concept, we are engineering and characterizing a series of novel oncolytic adenoviruses that will improve the specificity and effectiveness of the original construct.
We also study combinations of viral oncolysis and conventional therapy. In this regard, Dr. Alonso (Neuro-Oncology) and I reported that oncolytic adenoviruses increase the effect of temozolomide and mTOR inhibitors. We are working now to produce enough preliminary data for the development of a Phase I clinical trial combining Delta24 and temozolomide for the treatment of cancer patients. In collaboration with Dr. Lang (Neurosurgery) and Dr. Jiang (Neuro-Oncology), a translational effort to target cancer stem cells using oncolytic adenoviruses is underway. Importantly, we found that adenoviral replication in brain tumor stem cells resulted in the induction of autophagy (a type of cell death), opening research avenues to develop effective therapies in apoptosis-resistant tumors.
In collaboration with Dr. Gomez-Manzano (Neuro-Oncology), I have developed a new transgenic animal model by overexpressing E2F1 in both neural stem cells and mature astrocytes. The E2F1-mice showed a wide variety of brain tumors including gliomas. This model is the first direct evidence that E2F1 is an oncogene in gliomas and offers opportunities to address mechanistic hypotheses about tumorigenesis and tumor maintenance in gliomas as well as serving as a new animal model for the testing of anti-glioma drugs.
Gomez-Manzano C, Jiang H, Alonso MM, Yung WKA, Fueyo J. Gene Therapy. In : Neuro-Oncology. Handbook of Clinical Neurology, 3rd Edition. Eds: Grisold W, Siffietti R. Elsevier, Edinburgh, UK. (in press).
Jiang H, Gomez-Manzano C, Aoki H, Alonso MM, Kondo S, McCormick F, Korn M, 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, 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.
Alonso MM, Cascallo M, Gomez-Manzano C, Jiang H, Bekele NB, Perez-Gimenez A, Lang F, Piao Y, Alemany R, Fueyo J. ICOVIR-5 shows E2F1-addiction and potent anti-glioma effect in vivo. Cancer Res, 2007 Sep 1;67(17):8255-63.
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, 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. Review.
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.