Volume 11, Nº 5 (2011)

Introduction: This review provides an overview of the molecular mechanisms and pathways known to enhance development and progression of pancreatic ductal adenocarcinoma (PDAC). Results: Today, the concept that progression of epithelial precursor lesions leads to invasive PDAC as a result of accumulating mutation in K-ras, p16INK4A, p53 and Smad4 is widely accepted. Multiple signaling pathways that PDAC utilizes to acquire its tumorigenic features have been identified. Recent data suggest that reactivated developmental signaling pathways play a role in oncogenesis of PDAC. Furthermore, it is now clear that the tumor microenvironment actively promotes invasion and tumor growth through a complex of interactions of different cellular components. Conclusion: PDAC is still a challenging entity for physicians and scientists. Despite of recent advances in understanding its molecular biology, treatment options remain limited. Distinct tumor stroma interactions and apoptotic resistance lead to frequent failure of current chemotherapy. An early and aggressive tumor infiltration in combination with a late diagnosis prevents successful surgical therapy. Thus, our primary goal remains to translate the increasing knowledge of molecular pathogenesis of this disease into successful therapeutic strategies. Apart from tumor cell biology, the complex interactions of PDAC cells with their microenvironment have to be focus of future molecular research.

Insulin-like growth factor-1 (IGF-1) leads via its receptor IGF-1R to the activation of the PI3K/Akt pathway, providing antiapoptotic signals to pre-malignant and malignant cells. In pancreatic cancer, IGF-1 and its receptor are constitutively overexpressed. Mammalian target of rapamycin (mTOR) is the main mediator of mitogenic stimuli transduced by PI3K/Akt. Interestingly, inhibition of mTOR activates PI3K/Akt by up-regulating IGF-1R signaling. Several targeted agents have been developed to inhibit the activity of IGF-1 or to block IGF-1R. These pharmaceuticals may offer additional ways of stimulating apoptosis in neoplastic cells. Yet, there are difficulties in targeting this pathway: The ideal anti-cancer drug target is expressed only in cancer cells; however, IGF-1 and its receptor IGF-1R are ubiquitously expressed throughout the body. Moreover, when using antibodies against IGF-1R, the structurally similar insulin receptor might also be blocked, leading to hyperglycemia as a severe side effect. There are currently several phase I/II trials investigating IGF-1 and its receptor as a drug target in various kinds of cancer. Specifically, therapeutic effects on pancreatic cancer by combining a humanized monoclonal antibody against IGF-1R with other chemotherapeutics are being investigated. To improve the clinical outcome of mTOR inhibitors such as everolimus, it has been suggested to use combination therapies of mTOR inhibitors and IGF-1/IGF-1R inhibitors. In theory, this would counterbalance the feedback effects of mTOR inhibition on IGF-1 signaling. In conclusion, IGF-1 and its receptor are promising new drug targets in cancer therapy. Combination therapies of IGF-1/IGF-1R inhibitors and mTOR inhibitors could improve the clinical outcome.

The Neuropilin receptors are increasingly recognized as receptors for vascular endothelial growth factors like VEGF-A and VEGF-C as well as other important growth factors like HGF and FGF in human vasculature and in tumor cells. More and more studies show an important role of Neuropilin in cancer biology suggesting that these transmembrane proteins might be an emerging target for new therapies in different subsets of cancer. Interestingly, blocking the adaptor protein GIPC1/Synectin that interacts with Neuropilin might be another interesting avenue for therapy. This review summarizes unfolding scientific data on these receptors and its interacting protein GIPC1/Synectin as molecular targets for therapy in pancreatic ductal adenocarcinoma.

Pancreatic cancer has one of the poorest prognoses among all cancers partly because of its silent nature and tendency for late discovery but also because of its persistent resistance to chemotherapy. At present there are very limited treatment alternatives for pancreatic cancer, hence the need to develop novel and more efficient drugs. It is well known that mutations in K-Ras oncogene accumulate early in the disease progression and occur in almost all of pancreatic ductal adenocarcinomas (PDAC). A key downstream target of the Ras family is phosphoinositide 3-kinase (PI3K), the enzyme responsible for generation of 3-phosphorylated phosphoinositides and activation of Akt (Protein Kinase B/Akt). The PI3K/Akt pathway is involved in inhibition of apoptosis and stimulation of cell proliferation and it has been estimated that at least 50% of all cancer types are related to deregulation of this signalling pathway. In this review we will discuss how the PI3K/Akt/mTOR signalling network is altered in pancreatic cancer and further give an overview of preclinical and clinical studies where this pathway has been targeted.

Obesity, now a worldwide epidemic, causes myriad medical problems. One of the most significant obesity-related problems is the well-recognized relationship between obesity and various malignancies, including pancreatic cancer. Pancreatic cancer is a devastating disease – the annual death rate nearly approximates its incidence. While surgical extirpation provides the best chance at long term survival, systemic therapy is largely ineffective: even those patients undergoing successful operative resection have only approximately 20% 5-year survival. These poor outcomes are largely a consequence of poor understanding of tumor biology. Clearly, identification of novel treatment strategies is of paramount importance; investigation of pancreatic cancer biology from the novel aspect of obesity offers the potential to identify unique therapeutic targets. This manuscript reviews the epidemiology, clinical findings, and putative basic science mechanisms underlying obesity-related pancreatic cancer.