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 programme is designed to generate and use various animal and cellular models to systematically discover and ascribe functions of genes and gene products identified in genome wide analyses. This will contribute to 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.
We have finalized the selection of candidate genes for in-depth analysis based on in vitro experimental data. Detailed in vitro and in vivo results for some candidates have already been published, additional work is ongoing. A pre-clinical trial with an inhibitor against candidate gene TTK (WP2) has been started; moreover, a clinical trial with an agent targeting specific metabolic characteristics of cancer stem cells (WP3) has been initiated.
- Key Objective 2: Development of efficient, standardised and reliable tools, standardised operating procedures and technologies for phenotyping (WPs 1-7):
CAM-PaC generates in vitro and in vivo models for systematic functional characterisation of target genes as models for cross-sectional and longitudinal studies of carcinogenesis in the pancreas, and to validate predictive diagnostic and therapeutic approaches. A central goal of this project is to implement novel technologies for temporal and spatial control of transgene expression in genetically engineered mouse models (WP1) allowing for tissue-specific expression and control of target genes independently and in a reversible manner. We have established a first novel system for transgene control through Erythromycin-responsive elements in vivo (ongoing).
Furthermore, 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 in the 2nd reporting period. Our team used these for coordinated phenotyping analysis in period 3 and continues to do so (see below). We have also developed and validated new technologies for in vivo functional imaging to conduct non-invasive analyses in animal models,(WP4), including advanced functional MRI techniques.
- Key Objective 3: Large-scale histopathological, metabolic and molecular phenotyping in model organisms and in vitro model systems (WPs 4,7, 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 tumor xenografts and genetically engineered mouse models.
Our team has developed novel workflows for next-generation sequencing-based analysis as well as metabolic profiling from extremely small sample sizes (WP8 &9). Wecontinue to use these new approaches to systematically analyse samples from the different model systems. Among others, our histopathological and molecular evaluation of primary tumor tissues and their corresponding xenografts is well advanced (WP7) and is now being combined with in vivo chemosensitivity data (WP6). In parallel, first metabolome profiles representing interstitial fluid derived from organotypic cultures (WP8) are available for integration with next-generation sequencing data 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 consortium’s major aim of the area of research of WP10. To this end, the necessary infrastructure as well as methods for integrating heterogeneous data from different sources and methodological approaches have been already established and standardized tools made available to the consortium. First models of protein and pathway interactions have been produced, and predictions derived from these models are currently being experimentally validated.