Community Research and Development Information Service - CORDIS

Periodic Report Summary 4 - CAM-PAC (Integrative Analysis of Gene Functions in Cellular and Animal Models of Pancreatic Cancer)

Project Context and Objectives:
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 is 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.
Therefore, the project will develop novel cellular and animal models, as well as novel strategies to analyse and integrate large scale metabolic, transcriptomic and genetic data from these models, in order to systematically identify, characterise and validate novel targets for therapeutic intervention and bioinformatic models for predictive diagnostics.
These will include:
1) Cell-based model systems utilising pancreatic tumour (stem) cell lines with altered expression of target genes will be used to identify molecular functions, assess affected signalling pathways, and monitor effects on tumourigenicity and clonogenic growth mediated by the target genes.
2) Genetically engineered mouse models (GEMM) with novel modes for temporal and spatial control of transgene activation will be produced to validate the roles of target genes in tumour initiation, progression and differentiation in vivo.
3) Patient-derived xenografts will be used in pre-clinical therapeutic trials to address the exceptionally high inter- and intratumour heterogeneity in human PDAC and to identify novel determinants of therapy resistance in individual tumours.
4) Large scale metabolomic, in addition to transcriptomic and genomic profiling of resulting cellular and animal phenotypes, will be performed in order to close the large gaps of knowledge that exist in this area.
5) Large scale data integration and modelling of clinical, histopathological, biological and genome-wide molecular data of primary and xenograft tumours to identify novel therapeutic targets and predictive models.

Dissemination of the project’s results will be achieved by:
- Reaching out to the scientific community, industry, patient organisations and other interested or potential stakeholders
- Disseminating results to the scientific community in the academic, healthcare and pharmaceutical sectors
- Fostering interaction and exchange with the scientific community and the public
- Identifying and valorising intellectual property rights generated in CAM-PaC
- Exploring possibilities to conduct clinical trials to overcome therapy resistance in pancreatic cancer
Project Results:
The scientific goals of the project are 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 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 (SOPs) 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.
Potential Impact:
Epidemiological data show that pancreas cancer incidence increased ~ 1.2% per year from 1999 to 2008 against the general trend of major cancers, and is projected to double by 2030, making PDAC incidence a global health challenge. Innovative diagnostic and therapeutic approaches based on genes and gene networks involved in tumour progression and therapy resistance identified in high throughput genome analyses are urgently needed and will have a great impact on prolonging survival and reducing suffering of pancreatic cancer patients.
CAM-PaC represents a coordinated effort to structure and integrate the Europe-wide academic and SME-research into tumour progression and therapy resistance of pancreatic cancer, which will have a major impact on the development of future therapeutic strategies. 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. Apart from the direct benefits for pancreatic cancer patients outlined above CAM-PaC will impact a number of important areas:
• Establishing a structured and comprehensive research platform for a systematic functional characterisation and validation of pancreatic cancer target genes clearly requires pan-European collaboration such as CAM-PaC.
• A central purpose of the programme is to stimulate innovation by ensuring close and productive interactions between groups with expertise in a range of areas that we consider central for progress in cancer research and medicine. The participating groups individually have strong track records in various aspects of innovative, translational research, which are shared among the whole consortium by cross-utilising numerous in vitro and in vivo platforms and resources such as:
a) genetically engineered mouse models as preclinical in vivo platforms,
b) large collections of clinical samples from pancreatic cancer patients,
c) collections of xenografts from primary pancreatic tumours as in vivo platform,
d) various in vitro models for medium- to high-throughput analyses.
• The combination of multiple levels of expertise from 11 leading groups and SME from 5 European countries will create a network that will foster reverse-translation of clinical findings in the GEMMs, the development of novel therapeutic strategies targeting genes or gene networks identified in high throughput genome-wide analyses and the rapid translation into clinical applications.
• One further benefit of the breadth of expertise among the partners brought together in this programme will be the wide dissemination of radically new technologies among the scientific community, both, geographically and by research fields.
• Exploitation of the technologies to be developed through CAM-PaC in research, healthcare, and the pharmaceutical industry is central to the purposes of this research programme. The collaboration between academic and SME partners will stimulate the expedient transfer of intellectual property generated in academia and can also promote the establishment of new SMEs.
• Novel compounds targeting genes or gene networks to be used alone or in combination with standard cytotoxic drugs such as gemcitabine will be among the healthcare applications generated in CAM-PaC. With our translational approach we will develop new molecular targeted therapies. This will open new markets and will consequently contribute to the generation of new jobs.
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