Malignant tumours of the pancreas, known as pancreatic carcinomas, remain among the most serious challenges in modern medicine. Although not among the most common tumours, they are among the most frequent causes of cancer-related deaths, with approximately 28,000 deaths per year in the USA (3) and 40,000 per year in Europe (13). There are currently no means for the reliable diagnosis of early stages and for curative treatment of late stages of the tumour.
The overall aim of this EU Framework Programme 6 Integrated Project is to make use of genetic profiles of pancreatic cancer and precursor lesions to improve the outcome of pancreatic cancer patients by providing novel and highly efficient molecular diagnostic tools. One of the major prerequisites in order to achieve this ambitious aim is an integrated multidisciplinary research approach, which enables a strong interaction between technology, biology and medicine to translate genome data into practical, clinical applications.
EU funding for the consortium was started Aug 2006 for three years, bringing together 19 European partners from academia and industry with long-standing interest in pancreatic cancer biology, diagnosis and treatment. Since the express goal of this consortium is to generate molecular diagnostic tools that will be ready for clinical applications in the course of the project, inclusion of Small and Medium sized Enterprises (SME) with a particular interest in developing molecular diagnostic tools was a special priority from the beginning.
- More about pancreatic cancer
Who is at risk of developing pancreatic cancer?
State of the art treatment approaches
- How can the outcome of pancreatic cancer patients be improved?
How is consortium work divided among the groups?
More about pancreatic cancer
Pancreatic ductal adenocarcinoma remains one of the most difficult cancers to treat. It is the commonest cancer affecting the exocrine pancreas. The majority of patients present with advanced disease resulting in a low resection rate especially outside of regional specialist units (1). Without resection, the overall median survival is 4 to 6 months with an estimated 5-year survival rate of 0.4% to 5% (2). Chemotherapy has only a modest effect in improving survival by just a few weeks or months (16). Molecular targeted therapies are presently being tested in multiple phase II and III studies, but the agents available to date have yet to prove that they effectively improve the outcome for pancreatic cancer patients (14).
Patients who undergo pancreatic resection demonstrate a median survival of 10-18 months and a five-year survival rate of 17-24%. The late presentation is responsible in part for the poor overall medium survival of 3-5 months and poor long-term survival rate of 0.4 to 5.0% (2, 15, 18).
Who is at risk of developing pancreatic cancer?
Intense efforts have been made to identify persons at risk for pancreatic cancer. In multiple studies, only smoking has consistently been identified as a relevant environmental risk factor for pancreatic cancer (17). A number of hereditary syndromes such as familial pancreatic cancer, hereditary pancreatitis and the Peutz Jeghers syndrome are associated with an increased risk for pancreatic cancer (19).
State of the art treatment approaches
Over the last few years, efforts have been directed towards the development of adjuvant therapies in an attempt to improve outcome. The ESPAC (European Study Group for Pancreatic Cancer) trials are the largest adjuvant trials for pancreatic cancer. Several members of the MolDiag-Paca consortium are centrally involved in these trials, in which some progress towards prolonged survival has been achieved (10, 11, 12).
However, surgical resection remains the only potentially curative treatment approach for pancreatic cancer patients. The success rate of surgical resection could be significantly improved if early forms or precursors of pancreatic tumours could routinely and reliably be detected.
A major research focus of the recent years has therefore been the identification of percursor lesions for pancreatic cancer. Recently, an international expert committee classified these precursor lesions on the basis of histological criteria into three grades of so-called Pancreatic Intraepithelial Neoplasia (PanIN; for detailed information on the PanIN classification see http://pathology.jhu.edu/pancreas_panin) (5). Molecular studies in the various PanIN grades support the PanIN progression model and show that the consecutive accumulation of genetic changes parallels the histological grade of neoplasia (4, 6, 7, 8, 20).
How can the outcome of pancreatic cancer patients be improved?
At present, standard imaging techniques such as endoscopic ultrasonography (EUS), spiral computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) are not able to reliably detect small cancerous lesions (<1 cm) (21). Furthermore, even small pancreatic carcinomas of around 1 cm in size are frequently already past curability. Detection of PanINs is virtually impossible with the standard diagnostic modalities. Thus, new diagnostic tools using novel technology and/or targeting cancer- or PanIN-specific genetic changes are urgently needed, in particular for the screening of risk populations such as kindreds from families with a genetic risk for pancreatic cancer. Since conventional diagnostic tools are presently insufficient, completely new diagnostic approaches must be developed.
Thus, a significant improvement of the outcome for pancreatic cancer patients can only be achieved by:
- a better definition and identification of patients at risk for pancreatic cancer to be included in novel screening approaches
- development of molecular diagnostic approaches targeting preneoplastic lesions or early pancreatic tumours
- translation of the catalogue of genetic alterations identified on the genome, transcriptome and proteome level in recent and ongoing high-throughput analyses into novel diagnostic procedures
- development of techniques allowing application of molecular tests in minimal amounts of patient material such as fine needle aspirates, pancreatic or duodenal juice, serum and urine
- development of molecular biology-based strategies for risk stratification of patients with pancreatic tumours, e.g. identification of patients with good or bad prognosis or of patients with a potential to respond to pharmacological treatment
It is expected that global differential genetic analyses on the genome, transcriptome and proteome level of PanINs, early and advanced tumours may help to identify genetic patterns associated with the individual progression steps. Combined with innovative diagnostic approaches such as molecular imaging technology or detection of minimal amounts of marker genes in secretions, these analyses will create the tools that are necessary to devise early diagnostic strategies for patients at risk. Equally important, the collection of aberrantly expressed genes and proteins generated by such analyses may prove instrumental to the identification of targets for innovative chemoprevention strategies, which may in the future replace the current only curative treatment option (surgery) by a pharmacological approach.
How is consortium work divided among the groups?
The emphasis of our project is a multidisciplinary research approach aimed at bringing basic knowledge forward to the application stage ("translational" approach), to enable real, consistent and coordinated progress at European level in medicine and improve the quality of life of patients at risk for, or suffering from, pancreatic tumours. The consortium of experts in this project will also provide a forum to discuss standardisation of treatment protocols and diagnostic procedures for pancreatic cancer. In addition, we will make contributions to epidemiological aspects of the disease in identifying populations at risk for pancreatic cancer, which will have a major benefit of the molecular diagnostic tools developed in this project. Another important aspect is age. Since pancreatic cancer is primarily a disease occurring late in life (age over 50-60 years), the project will have a particular impact on improving the health of the elderly population.
To this end, the work programme of this integrated project is organized in seven highly coordinated work packages which cover three major levels of experimentation (see below for an organisation chart):
Level 1: Data, patients, resources:
WP1: Epidemiology, Patients at risk, Patient resources, coordinated by JP Neoptolemos, William Greenhalf & N.Malats
WP2: Molecular alterations of preneoplastic lesions, early and advanced tumors: genomic, transcriptomic and proteomic profiles, coordinated by N.R. Lemoine and T. Crnogorac-Jurcevic
Level 2: Development of novel molecular diagnostic tools
WP3: RNA-based diagnostics, coordinated by M. Buchholz and T. M. Gress
WP 4: Proteome based diagnostics, coordinated by Eithne Costello & Stephan Hahn
WP 5: Epigenetics, coordinated by Jörg Hoheisel
WP 6: Novel Molecular Imaging tools based on single proteins identified in high-throughput approaches, coordinated by S. Hahn
Level 3: Clinical trials of novel molecular diagnostic tools:
WP 7: Prospective clinical trials of novel molecular diagnostic tools, coordinated by JP Neoptolemos
(click on Participants to see the expertise of each group)
Organization and relation of workpackages:
WP1-Epidemiology & Risk Populations
WP1 will provide the patient resources required to develop and validate molecular diagnostic tools. Among other things this will include: Resected tissue samples for histological analyses and standardized histological diagnosis by expert reference pathologists. Moreover, WP1 will generate and collect sample resources for other workpackages (frozen/cryopreserved tissue; serum; plasma; and urine; DNA and RNA from these clinical samples and tissue arrays including arrays of tissue containing PanIN lesions, samples from a mouse model of pancreatic cancer).
The workpackage also includes registration of high-risk patients for recruitment to clinical trials, quantification of age related risk of cancer in patients at high-risk to increase the power of clinical trial (see WP7) and ultimately aid in patient screening.
Furthermore, WP1 will carry out molecular epidemiology; using DNA from "sporadic" pancreatic cancer patients to analyse the influence of gene-environment interactions on cancer risk.
WP2-Profiles of Molecular Alterations of PanINs, Early and Advanced Pancreatic Tumours
WP2 will generate and collect data on genome, transcriptome and proteome profiles of preneoplastic lesions, early and advanced tumors, other exocrine tumours, as well as prognostic and therapeutic tumour subgroups identified from analysis of the ESPAC1 and ESPAC3 clinical trials of chemotherapy in pancreatic cancer. These data will be stored in a central database to be accessed by all partners in this IP to select individual target genes or signatures suitable to develop molecular diagnostic and prognostic tools.
In this workpackage we want to channel all approaches by participants in this IP to use RNA based diagnostics to develop molecular diagnostic tools for minimal amounts of clinical material. We will make use of molecular data accumulated in WP2 to select diagnostic target genes and of resources and patients provided in WP1 to train, test and validate diagnostic assays. This will involve approaches on 3 diagnostic levels: I) Differential diagnosis of tumours diagnosed in the pancreas using conventional imaging modalities ("class prediction"), II) Risk stratification of patients with ductal adenocarcinoma of the pancreas to
allow individualized treatment decisions in an adjuvant and palliative setting ("class discovery") and III) Screening of patients at risk for preneoplastic lesions and early tumours.
We aim in this workpackage to carry out a variety of advanced proteomic analyses to detect and identify proteomics-based diagnostic biomarkers of pancreatic cancer in serum, pancreatic juice and urine. We will utilise the patient resources from WP1 for biomarker discovery and validation. The novel diagnostic tools that are generated as a result of this workpackage will be put forward for advanced analyses and trialing in WP7.
The major objective of this project is the provision of a set of epigenetic markers for diagnostic and prognostic purposes. A set of about 500 genes will be defined from existing data, which will be analysed in detail with respect to methylation variations in their promoter regions and the first exon. Both primary samples taken from tumour biopsies or tissue samples as well as serum samples will be analysed. Also, levels of promoter methylation in DNA from pancreatic juice samples will be measured and compared to levels in matched tissue. Once an array has been established functionally, analyses will be performed in collaboration with Asper Biotech (Tartu, Estonia).
Novel Molecular Imaging tools based on proteins identified in high-throughput approaches. The aim of this WP is to develop and evaluate molecular imaging techniques in animal models for the early diagnosis of pancreatic ductal adenocarcinoma and its precursor lesions (PanINs).
We will develop peptide/small molecule type or enzyme activatable probes for in vivo imaging reagents by high throughput screening of small molecule and peptide libraries. Furthermore, we will produce the selected imaging compounds through synthesis of appropriate precursor molecules for radio-/fluorochrome labeling or automated peptide synthesis with the required modifications necessary for radio-/fluorochrome labeling. After successful in vitro evaluation, labelling of ligands and peptides will be performed. All produced compounds will be evaluated by in vivo imaging in a small animal PET or FMT scanner.
WP7-Clinical Trials of Novel Molecular Diagnostic Tools
The aim of WP 7 is to evaluate the suitability and applicability of diagnostic tools (both those already existing and provided by partners in the IP, e.g. diagnostic arrays) for clinical use in the diagnosis of pancreatic cancer. This WP also aims to determine which of the diagnostic tools can be used as indicators of other disease parameters, e.g. disease progression.