RNAi Global Initiative - Vrije University Medical Center (VUMC)

HOME MEMBER LOGIN ABOUT US CONTACT MEMBER LIST

Vrije University Medical Center (VUMC)

	Victor van Beusechem

	Victor van Beusechem, Ph.D., is head of the section Oncogenomics and director of the RNA Interference Functional Oncogenomics Laboratory in the Department of Medical Oncology at the VUmc Cancer Center Amsterdam. He studied for his Ph.D. degree at the Institute for Applied Radiobiology and Immunology TNO in Rijswijk, where 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. in gene therapy at the University of Leiden in 1993. From 1993 to 1998, he was Senior Scientist at Introgene BV (now Crucell Holland BV) in Leiden, 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. The section Oncogenomics exploits gene expression modulation technologies to study the biology of cancer and to improve cancer therapy. This includes designing and evaluating oncolytic adenoviruses for cancer therapy. Significant advancement has been made in redirecting virus entry into cancer cells via alternative receptor molecules. An important breakthrough in making oncolytic adenoviruses more 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 most cancer cell lines of various tissue origins. Improved anti-cancer efficacy was confirmed in animal models. In addition, cell lines expressing p53 inhibitors MDM2 or HPV-E6 could be made more vulnerable to oncolytic adenovirus by expressing degradation-resistant p53 variants that do not bind to these inhibitors. We will exploit large-scale siRNA library screening for comprehensive identification of host cell factors that influence oncolytic virus replication in different types of cancer cells. Oncolytic adenoviruses with replication-specific marker gene expression cassettes were constructed for use in these library screens. In a proof-of-concept study, we already 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 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. 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. 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 Back to VUMC