| |
Victor van Beusechem, Ph.D., is head of the section Oncogenomics and director of the RNA Interference Functional Oncogenomics Laboratory (RIFOL) in the Department of Medical Oncology at the VUmc Cancer Center Amsterdam. From 1987 to 1993, he developed a hematopoietic stem cell gene therapy procedure for severe combined immunodeficiency using recombinant retrovirus vectors expressing the human ADA gene. He was involved in bringing this treatment from the bench to the bedside, with the procedure finally being tested in patients. He received his Ph.D. (cum laude) at the University of Leiden in 1993. From 1993 to 1998, he was Senior Scientist at Introgene BV (now Crucell Holland BV), where he initiated research on pseudotyping and targeting adenovirus vectors for gene therapy and vaccination. In 1998, he continued his research at the VUmc, applying recombinant viruses to treat cancer. He was awarded a research fellowship of the Royal Netherlands Academy of Arts and Sciences (2001-2006) and received the Greiner Award 2000 from the Dutch Society of Gene Therapy. Since 2008, Victor van Beusechem is Chief Scientific Officer of ORCA Therapeutics, a biopharmaceutical company focusing on the development of new anti-cancer treatments using oncolytic replication competent agents.
The section Oncogenomics/RIFOL exploits gene expression modulation technologies to study the biology of cancer and to improve cancer therapy. Emphasis is on identifying genes involved in resistance to current and experimental anti-cancer therapies. The RIFOL serves as a VUMC core facility for RNAi library screening. Furthermore, we are designing and evaluating oncolytic adenoviruses as potential new anti-cancer agents. Significant advancement has been made in redirecting virus entry into cancer cells via alternative receptor molecules. An important breakthrough in making oncolytic adenoviruses potent cancer cell killers was the observation that restoring defective p53 functions in cancer cells accelerated virus-induced cell lysis. A virus expressing exogenous wild type p53 was more effective in killing cancer cell lines, primary cancer specimens and xenograft tumors of various tissue origins. A lead product p53-expressing adenovirus is currently being developed towards clinical testing.
Currently, we exploit large-scale siRNA and miRNA library screening for comprehensive identification of host cell factors that influence oncolytic virus replication in cancer cells. Oncolytic adenoviruses with replication-specific marker gene expression cassettes were constructed for use in these library screens. Candidate targets identified in the screens are being validated. Our next step will be to incorporate RNAi-inducing molecules into the oncolytic adenovirus genome. In a proof-of-concept study, we showed that the RNAi machinery remains intact in human cancer cells during oncolytic adenovirus replication. An adenovirus expressing shRNA silenced its target during cancer-selective replication.
Selected Publications
Schagen, F.H.E., Graat, H.C.A., Carette, J.E., Vellinga, J., Van Geer, M.A., Hoeben, R.C., Dermody, T.S., Van Beusechem, V.W. (2008) Replacement of native adenovirus receptor-binding sites with a new attachment moiety diminishes hepatic tropism and enhances bioavailability in mice. Hum. Gene Ther., 19:783-794.
Graat, H.C.A., Van Beusechem, V.W., Schagen, F.H.E., Witlox, M.A., Kleinerman, E.S., Helder, M.N., Gerritsen, W.R., Kaspers, G.J.L., Wuisman, P.I.J.M. (2008) Intravenous administration of the conditionally replicative adenovirus Ad5-D24RGD induces regression of osteosarcoma lung metastases. Mol. Cancer, 7:9.
Graat, H.C.A., Carette, J.E., Schagen, F.H.E., Vassilev, L.T., Gerritsen, W.R., Kaspers, G.J.L., Wuisman, P.I.J.M., Van Beusechem, V.W. (2007) Enhanced tumor cell kill by combined treatment with a small-molecule antagonist of MDM2 and adenoviruses encoding p53. Mol. Cancer Ther., 6:1552-1561.
Carette, J.E., Graat, H.C.A., Schagen, F.H.E., Mastenbroek, D.C.J., Rots, M.G., Haisma, H.J., Groothuis, G.M.M., Schaap, G.R., Bras, J., Kaspers, G.J.L., Wuisman, P.I.J.M., Gerritsen, W.R., Van Beusechem, V.W. A conditionally replicating adenovirus with strict selectivity in killing cells expressing epidermal growth factor receptor, Virology, 361:56-67.
Schagen, F.H.E., Wensveen, F.M., Carette, J.E., Dermody, T.S., Gerritsen, W.R., Van Beusechem, V.W. (2006) Genetic targeting of adenovirus vectors using a reovirus σ1-based attachment protein. Mol. Ther., 13:997-1005.
Graat, H.C.A., Witlox, M.A., Schagen, F.H.E., Kaspers, G.J.L., Helder, M.N., Bras, J., Schaap, G.R., Gerritsen, W.R., Wuisman, P.I.J.M., Van Beusechem, V.W. (2006) Different susceptibility of osteosarcoma cell lines and primary cells to treatment with oncolytic adenovirus and doxorubicin or cisplatin. Br. J. Cancer, 94:1837-1844.
Heideman, D.A.M., Steenbergen, R.D.M., Van der Torre, J., Scheffner, M., Alemany, R., Gerritsen, W.R., Meijer, C.J.L.M., Snijders, P.J.F., Van Beusechem, V.W. (2005) Oncolytic adenovirus expressing a p53 variant resistant to degradation by HPV E6 protein exhibits potent and selective replication in cervical cancers. Mol. Ther., 12:1083-1090.
Van Beusechem, V.W., Van den Doel, P.B., Gerritsen, W.R. (2005) Conditionally replicative adenovirus expressing degradation-resistant p53 for enhanced oncolysis of human cancer cells overexpressing MDM2. Mol. Cancer Ther., 4:1013-1018.
Oosterhoff, D., Pinedo, H.M., Witlox, M.A., Carette, J.E., Gerritsen, W.R., Van Beusechem, V.W. (2005) Gene-directed enzyme prodrug therapy with carboxylesterase enhances the anti-cancer efficacy of the conditionally replicating adenovirus AdΔ24. Gene Ther., 12:1011-1018.
Carette, J.E., Graat, H.C.A., Schagen, F.H.E., Abou El Hassan, M.A.I., Gerritsen, W.R., Van Beusechem, V.W. (2005) Replication-dependent transgene expression from a conditionally replicating adenovirus via alternative splicing to a heterologous splice acceptor site. J. Gene Med., 7:1053-1062.
Geoerger, B., Vassal, G., Opolon, P., Dirven, C.M.F., Morizet, J., Laudani, L., Grill, J., Giaccone, G., Vandertop, P.W., Gerritsen, W.R., Van Beusechem, V.W. (2004) Oncolytic activity of p53-expressing conditionally replicative adenovirus AdΔ24-p53 against human malignant glioma. Cancer Res., 64:5753-5759.
Carette, J.E., Overmeer, R.M., Schagen, F.H.E., Alemany, R., Barski, O., Gerritsen, W.R., Van Beusechem, V.W. (2004) Conditionally replicating adenoviruses expressing short hairpin RNAs silence the expression of a target gene in cancer cells. Cancer Res., 64:2663-2667.
Van Beusechem, V.W., Mastenbroek, D.C.J., Van den Doel, P.B., Lamfers, M.L.M., Grill, J., Würdinger, T., Haisma, H.J., Pinedo, H.M., and Gerritsen, W.R. (2003) Conditionally replicative adenovirus expressing a targeting adapter molecule exhibits enhanced oncolytic potency on CAR-deficient tumors. Gene Ther., 10:1982-1991.
Van Beusechem, V.W., Van den Doel, P.B., Grill, J., Pinedo, H.M., and Gerritsen, W.R. (2002) Conditionally replicative adenovirus expressing p53 exhibits enhanced oncolytic potency. Cancer Res., 62: 6165-6171.
Van Beusechem, V.W., Grill, J., Mastenbroek, D.C.J., Wickham, T.J., Roelvink, P.W., Haisma, H.J., Lamfers, M.L.M., Dirven, C.M.F., Pinedo, H.M., and Gerritsen, W.R. (2002) Efficient and selective gene transfer into primary human brain tumors using single-chain antibody-targeted adenoviral vectors with native tropism abolished. J. Virol., 76:2753-2762.
Contact Details
Victor W. van Beusechem, Ph.D.
Department of Medical Oncology
VUmc Cancer Center Amsterdam
P.O. Box 7057
1007 MB Amsterdam
the Netherlands
Phone: +31.20.444.2162
Fax: +31.20.444.2126
Email
Web - Gene Therapy
|
