Improving cancer specificity and efficacy of PV-based therapies
Table of Contents
Our mission is to fight cancer. Our major goal is to develop novel anticancer therapies based on oncolytic parvoviruses which are efficient, specific and safe. We are committed to excellent science conducted rigorously but with great enthusiasm. To achieve our goals we will create a supportive environment that promotes positive interactions and cooperation between Team members, built on the reciprocal respect of each individual personality. Our motto is: we will do our best but there is always room for improvement.
| © Tom Holz (email@example.com)
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 (1, 2). 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 pancreatic carcinomas and gliomas as tumour models we are modifying PV 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 (3, 4) to developing chimeric viruses (5) or modifying their capsids for increased affinity to tumour cells (6). We are also designing new therapeutic protocols by combining oncolytic PV with epigenetic modulators (7) or pro-apoptotic BH3 mimetics (unpublished results).
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 initiated 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 and the mechanisms underlying PV-cytotoxicity. This valuable information can be exploited for improving our PV-based anti-cancer strategies.
We discovered that H-1PV through its non-structural protein NS1 induces intracellular accumulation of reactive oxygen species (ROS) leading to DNA damage, apoptosis and lysis of cancer cells (8). We are interested in further characterizing H-1PV-mediated cancer cell death.
References and selected publications:
1: Nüesch JP, Lacroix J, Marchini A, Rommelaere J. (2012). Molecular pathways: rodent parvoviruses--mechanisms of oncolysis and prospects for clinical cancer treatment. Clin Cancer Res. 18:3516-23. PubMed PMID: 22566376.
2: Marchini A,Bonifati S, Scott EM, Angelova AL and Rommelaere J (2015). Oncolytic parvoviruses: from basic virology to clinical applications. Virology J. 12:6 DOI 10.1186/s12985-014-0223-y.
3: El-Andaloussi N, Endele M, Leuchs B, Bonifati S, Kleinschmidt J, Rommelaere J,Marchini A. (2011). Novel adenovirus-based helper system to support production of recombinant parvovirus. Cancer Gene Ther. 18:240-9.PubMed PMID: 21102423.
4: El-Andaloussi N, Leuchs B, Bonifati S, Rommelaere J, Marchini A.(2012). Efficient recombinant parvovirus production with the help of adenovirus-derived systems. J Vis Exp. doi: 10.3791/3518. PubMed PMID: 22546707.
5: El-Andaloussi N, Bonifati S, Kaufmann JK, Mailly L, Daeffler L, Deryckere F, Nettelbeck DM, Rommelaere J, Marchini A. (2012). Generation of an adenovirus-parvovirus chimera with enhanced oncolytic potential. J Virol. [Epub ahead ofprint] PubMed PMID: 22787235.
6: Allaume X, El-Andaloussi N, Leuchs B, Bonifati S, Kulkarni A, Marttila T, Kaufmann JK, Nettelbeck DM, Kleinschmidt J, Rommelaere J, Marchini A. (2012). Retargeting of rat parvovirus H-1PV to cancer cells through genetic engineering of the viral capsid. J Virol. 86: 3452-65. PubMed PMID: 22258256.
7: Li J, Bonifati S, Hristov G, Martilla T, Valmary-Degano S, Stanzel S, , Aprahamian M, Grekova S, Raykov Z, Rommelaere J and Marchini A. (2013). Synergistic Combination of Valproic Acid and Oncolytic Parvovirus H-1PV as a Potential Therapy against Cervical and Pancreatic Carcinomas. EMBO Mol. Med. 10:1537-1555. PMID: 24092664
8: Hristov G, Krämer M, Li J, El-Andaloussi N, Mora R, Daeffler L, Zentgraf H,Rommelaere J, Marchini A. (2010). Through its nonstructural protein NS1, parvovirus H-1 induces apoptosis via accumulation of reactive oxygen species. J Virol. 84:5909-22. PubMed PMID: 20375165.
Gudrun Rappold, University of Heidelberg, Heidelberg
Andreas Kaufmann, Charité Medical University, Berlin
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
Prof. Peter Krammer, DKFZ, Heidelberg, Germany