The CAM-PaC project is focusing on four key objectives of research and implementation. The following summary provides an overview about what we have achieved so far.
- 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 is 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 are ongoing or have already been completed, resulting in several high-ranking publications. A pre-clinical trial with an inhibitor against candidate gene TTK (WP2) is ongoing; moreover, a clinical trial with an agent targeting specific metabolic characteristics of cancer stem cells (WP3) has been initiated. In addition, small-molecule screening for new inhibitors of selected target genes has been started.
- Key Objective 2: Development of efficient, standardised and reliable tools, standardised operating procedures and technologies for phenotyping (WPs 1-7):
A central goal of this project is to implement 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 continue to be used for coordinated phenotyping analysis (see below). 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 (published).
- 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, in WP7 expert molecular pancreatic pathologists are providing histopathological and molecular characterisation as well as SOPs for handling and exchange of materials from primary tumour xenografts and genetically engineered mouse models.
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 continue to be used to systematically analyse samples from the different model systems. Among others, histopathological and molecular evaluation of primary tumour tissues and their corresponding xenografts is well advanced (WP7) and is now being 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 is generating 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 is 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 already been established and standardized tools were made available to the consortium. First models of protein and pathway interactions have been established; the most advanced among these is a detailed model of the role of the WP2 candidate gene CFL1 in pancreatic cancer cells. Functional predictions derived from this model are currently being validated within WP2.