Table of Contents

Current Research

Our laboratory focuses on the development of novel strategies to treat cancer. We work on parvoviruses (PV), such as H-1PV and MVM, which are attractive agents for cancer therapy due to their apparent innocuousness in humans and their oncosuppressive properties. However, although parvoviruses replicate preferentially in cancer cells they can also infect normal tissues, and this sequesters a significant portion of the administered viral dose away from the tumor target. A second constrain is that these viruses are not always potent enough to arrest entirely tumour growth or cause a complete regression of neoplastic lesions. Using human papillomavirus (HPV) associated cervical carcinomas and gliomas as tumour models we are modifying these parvovirus to develop a new generation of viral vectors with high onco-specificity and onco-toxicity. We adopt many different strategies to achieve this, from arming the virus with additional oncolytic molecules to developing chimeric viruses or modifying their capsids for increased affinity to tumour cells. We are also designing new therapeutic protocols by combining oncolytic parvovirus with epigenetic modulators.

Future Projects and Goals

We will continue our research on the lines described before but are also starting novel projects at a more fundamental level. In collaboration with the IGBMC (FR), EMBL (DE) and Bioquant (DE), we will initiate an integrative biology research program which aims to characterize the early steps of infection of the H-1 oncolytic parvovirus using state of the art technologies such as high throughput siRNA library screening, ChIP on chip, microarrays and proteomics analysis. These studies will provide information essential to the understanding of the virus life cycle that we can further use in our PV-based anti-cancer strategies.

References and relevant publications:

1 El-Andaloussi N., Endele M., Leuchs B., Bonifati S., Kleinschmidt J., Rommelaere J. and Marchini A. (2010). Novel adenovirus based helper system to support production of recombinant parvovirus. Cancer Gene Therapy. In press.

2 Hristov G., Krämer M., Li J., El-Andaloussi N., Mora R., Daeffler L., Zentgraf H., Rommelaere J. and Marchini A (2010). Parvovirus H-1 through its non-structural protein NS1 induces apoptosis via accumulation of reactive oxygen species. Journal of Virology 84: 5909-22.

3 Marchini A., Häcker B., Marttila T., Hesse V., Emons J., Weiss B, Karperien M. and Rappold G.(2007).BNP is a transcriptional target of the short stature homeobox gene SHOX. Hum. Mol. Genet. 16: 3081-3087.

4 Marchini A., Rappold G., Schneider K.U. (2007). SHOX at a glance: from gene to protein. Arch. Physiol. Biochem. 113: 116-123.

5 Cornelis J.J., Lang S.I., Stroh-Dege A.Y., Balboni G., Dinsart C., Rommelaere J. (2004) Cancer gene therapy through autonomous parvovirus--mediated gene transfer. Curr. Gene Ther. 4, 249-61

6 Pisani, P., Bray, F. and Parkin, D. M. (2002) Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Int J Cancer 97, 72-81

7 Finzer P., Aguilar-Lemarroy A., Rosl F. (2002) The role of human papillomavirus oncoproteins E6 and E7 in apoptosis. Cancer Lett. 188, 15-24

8 Chen, Y. Q., Tuynder, M. C., Cornelis, J. J., Boukamp, P., Fusenig, N. E. and Rommelaere, J. (1989) Sensitization of human keratinocytes to killing by parvovirus H-1 takes place during their malignant transformation but does not require them to be tumorigenic. Carcinogenesis 10, 163-167

9 Faisst, S., Guittard, D., Benner, A., Cesbron, J. Y., Schlehofer, J. R., Rommelaere, J. and Dupressoir, T. (1998) Dose-dependent regression of HeLa cell-derived tumours in SCID mice after parvovirus H-1 infection. Int J Cancer 75, 584-589

Collaborations:

Gudrun Rappold, University of Heidelberg, Heidelberg

Andreas Kaufmann, Charité Medical University, Berlin

Vladimir Benes, EMBL, Heidelberg

Holger Erfle, Bioquant, Heidelberg, Germany

Laurent Brino, CGE/IGBMC, Strasbourg, France

Wolfgang Reffemberger, IGBMC, Strasbourg, France

Massimo Tommasino, IARC, Lyon, France

Christiane Mougin, CHU, Besançon, France