The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.

Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.

The nuclear factor of activated T cell (NFAT) proteins are a family of Ca 2 þ /calcineurin-responsive transcription factors primarily recognized for their central roles in T lymphocyte activation and cardiac valve development. We demonstrate that NFATc1 is commonly overexpressed in pancreatic carcinomas and enhances the malignant potential of tumor cells through transcriptional activation of the c-myc oncogene. Activated NFATc1 directly binds to a specific element within the proximal c-myc promoter and upregulates c-myc transcription, ultimately resulting in increased cell proliferation and enhanced anchorageindependent growth. Conversely, c-myc transcription and anchorage-dependent and -independent cell growth is significantly attenuated by inhibition of Ca 2 þ /calcineurin signaling or siRNA-mediated knock down of NFATc1 expression. Together, these results demonstrate that ectopic activation of NFATc1 and the Ca 2 þ /calcineurin signaling pathway is an important mechanism of oncogenic c-myc activation in pancreatic cancer.

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Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.