Institut Bergonié

Philippe Pourquier trained in Pharmacy and received his PhD in Biochemistry and Molecular Biology from the University of Bordeaux in 1996. After a post-doc at the US National Cancer Institute in Yves Pommier's laboratory, he obtained an INSERM research position and moved to the Bergonié Cancer Institute in 2001.
Danièle Montaudon trained in Pharmacy and received her PhD in Medical Sciences from the University of Bordeaux in 1984. She was appointed as a lecturer at the University in 1971 and is also in charge of a technical platform at the Bordeaux University Hospital. She joined the INSERM unit at the Bergonié Cancer Institute in 2001.
Nadine Houédé graduated in medicine from the University of Bordeaux in 1997. After a 2-year post-doc at the Princess Margaret Hospital in Ian Tannock's lab in Toronto, she was appointed as a medical oncologist at the Bergonié Cancer Institute in 2001. She received her PhD in Biostatistics from the University of Montpellier in 2008. She is the Head of the Urology Department and of the Early Phase Clinical Trials Unit at the Bergonié Cancer Institute.

Research projects:

The goal of our team is to identify and characterise new markers that predict the response of colon cancers and urologic cancers to anticancer drugs.

Identification of new predictive markers of cell sensitivity to anticancer agents

We have identified several genes whose modulation can affect cell sensitivity to topoisomerase I (Top1) inhibitors. We have focused on DNA-PKcs, which was recently reported by others to interact with Top1. We have now shown that it is the level of DNA-PKcs, rather than its kinase activity, that determines the sensitivity of cells to Top1 inhibitors in S-phase. For inhibitors like topotecan and irinotecan we suspect that one critical parameter is the ratio of DNA-PKcs to Top1. We plan to explore this hypothesis using cell lines and TMAs. The objectives of the study are: (i) to correlate the DNA-PKcs/Top1 ratio with sensitivity to Top1 inhibitors, (ii) to identify the key domains of interactions between both proteins in order, (iii) to develop drugs that block the DNA-PKcs/Top1 interaction, (iv) to identify regulators of the DNA-PKcs/Top1 complex, (v) to define the mechanism by which absence or downregulation of DNA-PKcs sensitises to Top1 inhibitors and (vi) to study the role of p21 and PARP-1 in this mechanism.

Identification of alternative therapies for the treatment of high grade prostate cancers based on their specific genomic profiling

In collaboration with the urology group, we have initiated a program to develop new therapies for high grade prostate cancer. These tumours can be distinguished from low grade tumours by the pattern of expression of 86 genes (True et al, 2006). We extracted from the NCI60 database the expression profiles of these genes and screened for those whose expression was correlated with the cellular sensitivity to a panel of drugs. For each candidate gene-drug pair we will validate whether silencing the gene by RNAi could indeed modulate the activity of the corresponding drug. This will coincidentally allow us to validate the use of the gene as a predictor of drug response. Given the lack of effective therapies for high grade prostate cancer, we hope this program will allow us to mount clinical trials using the genomic grade to select patients for treatment with drugs not previously used in prostate cancer.

Identification of predictive markers for tumour response to trabectedin (Et743) in soft tissue sarcomas

We are also involved in a project with the sarcoma group in which the goal is to identify markers that predict the response of sarcomas to trabectedin (Et743), an alkylating agent recently approved for use in this condition. We have recently identified a single nucleotide polymorphism (SNP) in the Nucleotide Excision Repair gene XPG that can predict the response to trabectedin. We are currently studying SNPs from other DNA repair genes, in order to identify a set of SNPs that could be used to select patients for treatment with trabectedin.

Role of TWIST as a marker of invasiveness in bladder cancer

Patients with invasive bladder cancer have a poor prognosis. The current classification is based on pathological criteria that do not allow clinicians to predict the degree of invasiveness of these tumours. Hence, it is crucial to identify new markers that predict invasiveness. Proteins involved in the epithelial-mesenchymal transition (EMT) are potential candidates given that EMT is a critical step in tumour invasion. EMT is characterized by loss of E-cadherin expression which is caused by promoter methylation or gene repression by transcription factors, such as TWIST, whose expression is known to be correlated with the metastatic potential of breast cancers. Our aim is to study the link between TWIST and other pathways involved in tumour progression. To do this, we will modulate TWIST expression and look for changes in Ras, Raf, MAPK, or AKT expression in bladder cell lines. We will also assess whether this modulation of TWIST expression sensitises bladder cancer cells to anticancer agents. We will also measure TWIST expression in Tissue MicroArrays in order to evaluate whether it could have a role in the management of superficial or invasive bladder tumours.

Publications:

Tautu M.T., Montaudon D., Palle K., Adachi N., Zanese M., Roulin C., Dutreix M., Gibson A.A., Bjornsti M.-A., Pourquier P. - The NHEJ-independent binding of DNA-PKcs to topoisomerase I alters cell sensitivity to camptothecin. EMBO J. In revision

Wallerand H, Robert G, Pasticier G, Ravaud A, Ballanger P, Reiter RE, Ferrière JM. The epithelial-mesenchymal transition-inducing factor TWIST is an attractive target in advanced and/or metastatic bladder and prostate cancers. Urol Oncol. 2009 Mar 7

Houede N, Thall PF, Nguyen H, Paoletti X, Kramar A. Utility-Based Optimization of Combination Therapy Using Ordinal Toxicity and Efficacy in Phase I/II Trials. Biometrics. 2009 Aug 10.

Verbiest V, Montaudon D, Tautu MT, Moukarzel J, Portail JP, Markovits J, Robert J, Ichas F, Pourquier P. Protein arginine (N)-methyl transferase 7 (PRMT7) as a potential target for the sensitization of tumor cells to camptothecins. FEBS Lett 2008 ; 582: 1483-9.

Montaudon D, Palle K, Rivory LP, Robert J, Douat-Casassus C, Quideau S, Bjornsti MA, Pourquier P. Inhibition of topoisomerase I cleavage activity by thiol-reactive compounds: importance of vicinal cysteines 504 and 505. J Biol Chem 2007 ; 282: 14403-12.

Le Morvan V, Longy M, Bonaïti-Pellié C, Bui BN, Houédé N, Coindre JM, Robert J, Pourquier P. Genetic polymorphisms of the XPG and XPD nucleotide excision repair genes in sarcoma patients. Int J Cancer 2006 ; 119: 1732-5.

Takebayashi Y., Pourquier P., Zimonjic D. B., Nakayama K., Emmert S., Ueda T., Urasaki Y., Kanzaki A., Akiyama S.-I., Popescu N., Kraemer K. H., Pommier, Y. - Transcription-coupled nucleotide excision repair-dependent antiproliferative activity of etceinascidin 743, a novel anticancer drug isolated from the caribbean sea squirt. Nat. Med. 2001, 7: 961-966