Kidney Cancer PNES Programme

General description

The kidney cancer PNES programme was funded by INCa between 2006 and 2008, amounting to a total budget of €1.4 million. Although financial support from the Institute ended in November 2008, the programme’s clinical trials are continuing.

This programme’s objective was to implement an integrated research approach bringing together clinical and basic studies in order to develop, evaluate and better understand the mechanisms at work in anti-angiogenic therapies.

The network that was created brought together 36 teams: 9 main teams participating in the steering committee and 23 clinical centres where the clinical trials and auxiliary studies were conducted. This programme is based on 3 lines of research: (1) biological studies, (2) the development of preclinical models for xenotransplantation and (3) the clinical trials along with their auxiliary studies (with regard to the clinical component of the project, the institute only funded the auxiliary studies). The sporadic and hereditary forms of kidney cancer (in particular, VHL disease) were studied from all these approaches.

Scientific advances

The object of the biological studies was the active mechanism and the signalling pathways of tumour angiogenesis as well as the response and resistance to anti-angiogenic treatments. These studies were conducted thanks to close collaboration between clinicians and researchers, in particular in the human tissue studies. Major findings related to:

• The signalling pathway “pVHL/HIF/aHIF/VEGF/angiogenesis” as well as mutations in tumour cells (Ladroue C. et al., NEJM, 2008)

• The role of cytokines (Khawan K. et al., Cancer Res., 2009)

• The role of energy metabolism and the microenvironment (G. Gasparre et al., Hum. Mol. Genet., 2008/Kroemer G. et Puyssegur J., Cancer Cell, 2008)

• Regulation of TREG lymphocytes in patients receiving anti-angiogenic treatment (pharmaceutical thesis)

• Comparison of VHL disease and the genomes of sporadic tumours (underway)

• Analysis of hereditary kidney cancers without the mutation on gene VHL (Woodward E.R. et al., Clin. Can. Res. , 2008): recommendation for an analysis of mutations on gene FLNC in addition to the analysis of mutations on gene VHL and the cytogenetic analysis.

As for the preclinical models, the technique of xenotransplantation of human tumours onto mice has been implemented. Tumour development in mice is effective on the initial attempt in over 25% of cases. Tumour xenotransplants from patients treated with anti-angiogenics have been tested, but the results of these experiments are not yet available. No xenotransplant from VHL tumours has ever been developed in SCID or nude mice. However, one experiment is currently underway using a high-grade VHL tumour.

With respect to clinical trials, all analysis techniques for auxiliary studies have been implemented: detection of mutations, VHL promoter hypermethylations and deletions; immunohistological characterisation of the molecular expression of the tumour for the VHL/HIF/VEGF pathway; quantification of VEGF isoforms and their receptors in plasma; quantification of bFGF, SDF1 and PDGF isoforms in plasma; quantification by flow cytometry of circulating endothelial progenitor cells.

Clinical trials (S-TRAC, PREINSUT and SUPAP) are still underway with ongoing patient recruitment. The start of the S-TRAC and PREINSUT studies was delayed due to a number of changes to the protocols and inclusion criteria.

Conclusions - Prospects

This programme brings together clinicians and researchers in the same research network spanning numerous disciplines. These interactions have resulted in significant advances in the fight against kidney cancer and should produce new fruitful collaborations in the future.

Although financial support from the Institute came to an end in November of 2008, the network created is still active and its members maintain close contact, which is producing new research proposal submissions.

As for clinical trials currently underway, their findings and analyses and their auxiliary studies should contribute to improvements in patient treatment and monitoring.