Pancreatic ductal adenocarcinoma (PDAC) is the 4th to 5th most common cause of cancer related deaths in the Western world and is virtually resistant to any conventional therapeutic regimens. It is thus a health problem with a major socioeconomic impact for any society. Despite enormous advances in the identification of molecular changes associated with the disease, new treatment options have not emerged. Thus, 5-year survival rates remain unchanged at a dismal of 6%, the lowest for all solid tumours.
The overall aim of CAM-PaC was to use a strongly SME-driven approach to contribute to solving the socioeconomic and health challenges of PDAC by an integrative and systematic functional analysis of pancreatic cancer candidate genes pre-selected and pre-characterised by members of the consortium in previous and ongoing high-throughput “omics” approaches. The scientific goals of the project were structured into 4 key objectives of research and implementation:
- Key Objective 1: Creation of a portfolio of new and validated therapeutic targets associated with human disease by use of various cellular and animal models (WPs 2 & 3):
The program was designed to generate and use animal and cellular models to systematically analyze functions of genes and gene products in order to attain a better understanding of the disease, furnish a portfolio of new and validated therapeutic targets, compounds and therapeutic strategies for PDAC and serve as the basis for a translation into clinical applications.
Detailed in vitro and in vivo analyses of a large number of candidate genes have been performed, resulting in several high-ranking publications. A pre-clinical trial with an inhibitor against candidate gene TTK (WP2) has been started and is ongoing; moreover, two clinical trials with agents targeting specific metabolic characteristics of cancer stem cells (WP3) have been initiated. In addition, small-molecule screening for new inhibitors of selected target genes has been performed or is ongoing.
- Key Objective 2: Development of efficient, standardised and reliable tools, standardised operating procedures (SOPs ) and technologies for phenotyping (WPs 1-7 ):
A central goal of this project was the implementation of novel technologies for temporal and spatial control of transgene expression in GEMM (WP1) allowing for tissue-specific expression and control of target genes independently and in a reversible manner. A first novel system for transgene control through Erythromycin-responsive elements has been established in vivo; mice carrying this novel system have been generated and are currently being analyzed. Further, a standardised collection of patient-derived xenografts (WP6) as well as advanced methods for in vitro culture of single cell-derived clones and defined co-culture (WP5) have been established and used for coordinated phenotyping analysis. New technologies for non-invasive in vivo functional imaging (WP4), including advanced functional MRI techniques, have been developed in animal models and successfully transferred to clinical practice for human patients.
- Key Objective 3: Large-scale histopathological, metabolic and molecular phenotyping in model organisms and in vitro model systems (WPs 4, 5, 6, 7, 8 & 9):
Comprehensive phenotyping is quintessential to take full advantage of the newly developed model systems as well as to validate their relevance for the human situation. To ensure standardisation, harmonisation and common ontology across different sites in the consortium, expert molecular pancreatic pathologists provided histopathological and molecular characterisation as well as SOPs for handling and exchange of materials from primary tumour xenografts and genetically engineered mouse models (WP7).
Novel workflows for next-generation sequencing-based analysis as well as metabolic profiling from extremely small sample sizes have been developed within WP9 & WP8, respectively, and used to systematically analyse samples from the different model systems. Among others, histopathological and molecular evaluation of primary tumour tissues and their corresponding xenografts (WP7) has been combined with in vivo chemosensitivity data (WP6), metabolome profiles and functional data from organotypic cultures (WP8), 3D growth assays (WP5) and next-generation sequencing data (WP9) from the same cells.
- Key Objective 4: Large scale data integration (WP10):
The CAM-PaC project has generated large amounts of diverse types of data on molecular and phenotypical traits of primary human tissues and in vitro and in vivo model systems of pancreatic cancer. Developing novel methods to utilise the knowledge that is generated on different levels and formulating scientific hypotheses from the comprehensive analysis of these data was the major aim of WP10. To this end, the necessary infrastructure as well as methods for integrating heterogeneous data from different sources and methodological approaches have been established and standardized tools made available to the consortium. Mathematical models of protein and pathway interactions have been established, and functional predictions derived from this model experimentally validated within WP2.
Overall, the work performed in CAM-PaC has resulted in ~90 publications in peer-reviewed journals as well as one patent already issued and several further patent applications in submission or preparation.