Strategies for discovering novel pancreatic cancer biomarkers

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in both men and women in Canada and the United States and has the most dismal survival rates among any solid malignancy. Most patients are diagnosed with pancreatic cancer once the disease has progressed into an advanced or metastatic stage, making the only curative approach of resection surgery impossible. The persistent delayed or missed diagnosis of pancreatic cancer can be attributed to the absence of early symptoms and the lack of efficient non-invasive screening or diagnostic tests in clinical practice. Given that earlier diagnosis is critical for ameliorating patients' survival rates, there is an urgent need for biomarkers with enough sensitivity and specificity to help diagnose pancreatic cancer early. Serological biomarkers provide a minimally invasive and efficient way of detecting pancreatic cancer, however, there is currently no marker with sufficient diagnostic sensitivity and specificity to identify early cancer patients. This review focuses on the classical tumor markers for PDAC as well as emerging markers. In addition, we will discuss an integrative proteomic approach used in our lab to identify a panel of biomarkers that have the potential to allow the early detection of PDAC.This article is part of a Special Issue entitled: From protein structures to clinical applications.

Figure 1. The need for additional new biomarkers

Two collaborative investigating groups suggested that it takes up to approximately 15–16 years from tumour initiation to the development of a parental clone, which eventually develops into subclones with metastatic potential. The chances of survival decline rapidly once the disease has progressed into later stages. The poor prognosis of this devastating disease is partly attributed to the poor diagnostic value of currently used biomarkers, resulting in the majority of patients being diagnosed at a point at which the tumour has acquired metastatic potential. Therefore, there is an urgent unmet need of new biomarkers to detect pancreatic cancer in its early stages to improve patient survival.

Figure 2. Integrative approach in identification of biomarker candidates and follow-up validation study using ELISA

We employed an integrative discovery platform that includes the comparison of proteomes of cell line conditioned media (CM), pancreatic juice, ascites and then filtered our candidates through mining publically available databases, ensuring tissue specificity which enabled the selection of the most promising candidates for verification [62, 63]. Of the derived candidates, ELISA, being the gold standard for analyzing serum proteins, was performed in plasma samples from pancreatic cancer patients and healthy controls for preliminary verification [62]. More recently, we identified additional candidates by identifying tissue-specific proteins using bioinformatics [71].