Project: Development of a canine melanoma pre-clinical model

The objective is to develop and characterize a new pre-clinical melanoma model using canine spontaneous melanoma. This industrial project, named MELANOModel, is motivated by five fundamental observations:_x000D__x000D_1) The increasing incidence of melanoma in humans and in pet dogs and the corresponding need to develop novel, targeted therapies for this pathology. Of all tumours, melanoma incidence ranks third in women. In Europe and the USA, the incidence and mortality of this highly aggressive cancer has increased 3- fold over the last 20 years (Purdue el al, 2008). _x000D_2) The urgent need to identify prognostic tools and predisposing genes in order to detect the tumour at its earliest stages and set up a dedicated follow up, adjust the treatments and anticipate fatal relapses. Melanoma predisposing genes have proven to be difficult to track down in humans (Nan et al., 2009), leaving the physiopathology of melanomas scarcely documented and efficient and specific prognostic markers are not yet available _x000D_3) The productivity crisis in the oncology research and development process in the pharmaceutical industry that translates into an unacceptably high failure rate of new cancer drug candidates (as much as 97% in human clinical trials), together with increasing development costs. (Kamb 2005, Benson 2006, Anisimov 2005)._x000D_4) The poor performance and insufficient clinical relevance of the currently-used pre-clinical models in oncology, i.e. COly rodent-based assays. This situation is COly due to three factors: the genetic and phenotypic distance between the rodent host and humans, the frequent use of genetically modified mice for cancer studies and finally the drift of the tumour cells that are being used, as they typically have been passaged for many generations. _x000D_5) Research efforts in comparative oncology and, more recently, in comparative genomics have clearly demonstrated that many spontaneous tumours in the dog are excellent models for the corresponding pathology in humans (review by Paoloni and Khanna 2008). In fact, the “canine model” has distinctive advantages over existing rodent models and we propose to use canine melanoma as a powerful comparative model for human melanoma. Considering the genetic heterogeneity and the variations in the clinical presentation and the biology of melanomas in human, we believe that purebred dogs, as quite homogeneous genetic isolates, can significantly help advance medical genetics. _x000D__x000D_The overall objective of the MELANOModel project is to perform a comprehensive comparative study of canine melanoma at the clinical, cellular and molecular level. This will involve morphology, histopathology, immunocytochemistry and genetic alterations in the tumour cells (somatic mutations and gene expression). Then primary canine cell cultures will be derived from these well characterized tumour types and the activity of different drugs on these cultures will be assessed. The validation of this pre-clinical screening step will allow a more efficient selection of compounds before their human clinical trials, a significant improvement over existing pre-clinical assays. An additional benefit of our strategy is the identification of cancer drugs potentially interesting for the treatment of melanoma in dogs, with the possible development of clinical trials in dogs affected by melanoma subtypes responding to specific drugs in culture. In fact, existing treatment options for canine melanoma are quite disappointing (Bergman, 2007). The different steps will be:_x000D__x000D_1. Collection of canine melanoma specimens through the already available veterinary networks_x000D_2. Melanoma staging, grading and prognostic factors (comparative pathology)_x000D_3. Characterization of genetic alterations in the tumour cells: identification of somatic mutations in tumour DNA and gene expression in tumour RNA, to identify new prognostic markers/therapeutic targets_x000D_4. Derivation of primary cell cultures_x000D_5. Development of an in vitro assay for drug testing _x000D_6. Translational research on human melanoma and the possibility to conduct canine clinical trials_x000D__x000D_The consortium that we have assembled brings together leading SMEs and academic laboratories with an existing working relationship and complementary expertise. The four Ps are recognized experts in areas of activity that include medicine and veterinary medicine, comparative pathology, genetics and genomics and molecular and cellular biology. They are all already implied in canine oncology studies (OncoBio Tek) or canine genetics analysis (DNA Vision and ULg) or both (CNRS-Rennes)_x000D__x000D_Anisimov V. et al. Nature Reviews Cancer 2005, 5:807-819._x000D_Benson J.D. et al. Nature 2006, 441:451-456._x000D_Kamb. A; Nature Reviews Drug Discovery 2005, 4:161-165._x000D_Nan et al. Int J Cancer. 2009. 125:909-17._x000D_Paoloni M. and Khanna C. Nature Reviews Cancer 2008, 8:147-156._x000D_Purdue M et al. J Invest Dermatol. 2008. 128:2905-8. _x000D_Bergman P. Clin Tech Small Anim Pract. 2007. 22:55-60. Review._x000D_

Acronym	MELANOModel (Reference Number: 5300)
Duration	01/11/2010 - 30/04/2014
Project Topic	The aim is to develop and characterize a new pre-clinical melanoma model using canine spontaneous melanoma accurately defined (at the cellular and molecular level) from which primary cultures will be derived. The activity of different cytotoxic drugs will be assessed on these cultures.
Project Results (after finalisation)	On genetic point of view, this project brings a contribution DNAVision to develop new services based on the newest sequencing technologies and to COtain its competitive position on the market of exome sequencing.
Network	Eurostars
Call	Eurostars Cut-Off 3

Project partner

Number	Name	Role	Country
4	Centre National de Recherche Scientifique	Partner	France
4	DNAVision AgriFood SA	Coordinator	Belgium
4	OncoBio Tek	Partner	France
4	Université de Liège	Partner	Belgium