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Investigators
Dr Steve Pereira, Institute of Hepatology, Department of Medicine, University College London
Dr John Timms and Dr Mark Weeks, Department of Gynaecological Oncology, EGA Institute for Women’s Health, University College London
Abstract of proposed work
The overall aim of this research is to undertake preliminary investigations to indicate whether testing serum for currently identified biomarkers of pancreatic cancer could be ultimately translated into the clinic in the form of blood tests for the diagnosis of pancreatic ductal adenocarcinoma (PDAC).
A small research grant has been awarded to begin systematic testing of previously identified possible biomarkers against an existing serum collection. They aim to establish the performance of identified proteins/peptides as early markers of PDAC using serum samples (the clear liquid that can be separated from clotted blood) from the UKCTOCS study. Currently, this collection contains serum samples from over 200,000 women collected over a 6 year period. Within this resource are serial serum samples from 104 women which pre- and post-date a diagnosis of PDAC. This represents an extremely important and rare resource with limited sample volumes. Potential biomarkers will be tested using this pre clinical resource to characterise the value of markers discovered from late stage cancers.
The investigators will apply a recently established semi-automated, C18 magnetic bead-based extraction platform linked to MALDI-TOF MS (Matrix Assisted Laser Desorption Ionisation Time-Of-Flight Mass Spectrometry) serum peptide profiling based on previous work by Villanueva et al (Anal. Chem., 2004 ). Using this platform, it has been shown that healthy and cancer serum samples could be accurately classified based upon changes in abundant serum peptides generated as a result of the actions of tumour-specific exopeptidases (enzymes) following clotting. This platform is used to search for serum peptide markers of ovarian cancer, and will be applied here in the same way to look for discriminatory peptide peaks which separate PDAC and control samples in a ‘discovery set’. Funding will be directed towards the cost of sample retrieval and biomarker testing within the UKCTOCS serum collection. In addition a new serum collection of PDAC, chronic pancreatitis and healthy controls will be established to generate a resource for the discovery of new biomarkers as part of future collaborative studies. It is imperative to establish reproducible protocols for such testing on control samples prior to tapping into this resource.
Background
Pancreatic ductal adenocarcinoma (PDAC), the most common exocrine pancreatic malignancy accounts for more than 80% of malignant neoplasms arising from the pancreas. Surgery, which provides the best survival rates, is only possible in about 10-20% of cases due to late presentation of the disease. When diagnosed, 40% of patients have established metastases and 40-50% already display locally advanced disease. There is therefore an urgent need to discover early biomarkers of PDAC that would enable early diagnosis, so that surgical therapy can be offered to a greater proportion of patients.
Summary of current knowledge
Given the relatively low occurrence of PDAC worldwide, candidate markers for population screening would require almost 100% specificity (ie only be present in people with pancreatic cancer) to avoid high false positive rates. In reality there is a distinct lack of candidate markers of PDAC that have been validated as suitable for population screening and a lack of follow-up investigations into such markers to define roles they may play in disease development. The current literature lists numerous candidate biomarkers of PDAC, but the majority, identified from late stage cases, have not been subject to vigorous independent validation and therefore, translation to the clinic is not at present realistic.
Where the work may lead to
In future, this work could lead to the validation and characterisation of existing and new biomarkers of PDAC highlighted in this pilot study. An in-depth understanding of the function of such markers may aid in their development as diagnostic and prognostic markers or suggest them as potential therapeutic targets. Also the methods developed here could be applied for the discovery of biomarkers of other diseases such as biliary tract cancer, for which a large prospective clinical database and biobank is being coordinated at UCLH.
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