Glioma Research Group

RESEARCH INTEREST
My interest is focused on development of novel strategies and vector systems for brain cancer gene therapy. Being relatively low in vivo efficiency of conventional gene delivery vector systems by delivering genes as therapeutic agents, clinical gene therapy trials have found significant shortcomings in achieve efficient gene delivery and significant lack of therapeutic efficacy in vivo. I am seeking to maximize the potential for achieving successful gene therapy especially for brain cancer by selecting the appropriate existing vector systems, and by developing a new generation of gene delivery vector systems.

1. Adenovirus vector mediated gene delivery has been demonstrated in clinical trials as a novel potential treatment for malignant gliomas. The coxsackie B virus and adenovirus receptor has been shown to function as an attachment receptor for multiple adenovirus serotypes, while the vitronectin integrins are involved in AdV internalization. In order to increase transgene activity in low and CAR-deficient glioma cells in vitro and in vivo, we used basic fibroblast growth factor (FGF2) as a targeting ligand to redirect adenoviral infection through its cognate receptor, FGFR1, which was shown to be expressed at high levels by all glioma cells.

2. We have developed murine leukemia virus (MLV)-based replication-competent retrovirus (RCR) vectors, and have demonstrated that such vectors are capable of highly efficient replicative spread and gene delivery throughout solid tumors in the brain. Due to its natural inability to infect quiescent cells, MLV infection is selective for actively dividing tumor cells, and as this virus can stably integrates into the genome of the tumor cell, RCR vectors achieve not only efficient but also persistent infection in vivo, allowing the virus to follow tumor cells even as they migrate and form metastatic foci. The following vector systems are available in our lab now: RCR-TK/Ganciclovir, RCR-PNP/fludarabin, and RCR-CD/5-Florocytosine.

SELECTED PUBLICATIONS
W. Weijun, C. Tai , N. Kasahara, T.C. Chen. 2003. Highly efficient and tumor-restricted gene transfer to malignant gliomas by replication-competent retroviral vectors. Human Gene Therapy Vol. 14 117-127.

C.Tai, W. Wang, T.C. Chen and N. Kasahara. 2005. Single-Shot, Multicycle Suicide Gene Therapy by Replication-Competent Retrovirus Vectors Achieves Long-Term Survival Benefit in Experimental Glioma. Molecular Therapy Vol. 12

A. Kardosh, W. Wang, J. Uddin, N.A. Petasis, F.M. Hofman, T.C. Chen. A. H. Schönthal. 2005. 1,5 Dimethyl-celecoxib (DMC), a derivative of celecoxib that lacks cyclooxygenase-inhibitory function, potently mimics the anti-tumor effects of celecoxib on Burkitt’s lymphoma in vitro and in vivo. Caner Bio. & Therapy Vol. 4 571-582.

P. Pyrko, W. Wang, F.S. Markland, S.D. Swenson, S. Schmitmeier, A.H. Schönthal, T.C. Chen. Contortrostatin, a snake venom disintegrin, inhibits invasion and prolongs survival in a rodent model of glioma. Journal of Neurosurgery.

W. Wang, N. Zhu, J. Chua, , S. Swenson, F. K. Costa, S. Schmitmeier, B.A. Sosnowski, T. Shichinohe, N. Kasahara, T.C. Chen. Retargeting of adenoviral vector using FGF2 ligand for malignant glioma gene therapy. Journal of Neurosurgery.

A. Kardosh, M. Blumenthal, W. Wang, T.C. Chen, A.H. Schönthal. 2004. Dexrease in Cyclin-Dependent Kinase Activity Via the Transcription Down-Regulation of Cyclin A and Cyclin B Expression in Human Glioblastoma Cell Lines by the Cox-2 Specific Inhibitor Celecoxib-Comparison to Other NSAIDs. Caner Bio. & Therapy Vol 3 055-062.

C. Tai, W. Wang, C.R.Logg, W.B. Parker, J.S. Hong, Y. Li, E.J. Sorscher, T.C. Chen, N. Kasahara. Enhanced efficiency of prodrug activation therapy by tumor-selectively replicating retrovirus vectors armed with the Escherichia coli purine nucleoside phosphorylase gene. Human Gene Therapy Submitted.