Pancreatic cancer: molecular pathogenesis and new therapeutic targets

Abstract

Patients with pancreatic cancer normally present with advanced disease that is lethal and notoriously difficult to treat. Survival has not improved dramatically despite routine use of chemotherapy and radiotherapy; this situation signifies an urgent need for novel therapeutic approaches. Over the past decade, a large number of studies have been published that aimed to target the molecular abnormalities implicated in pancreatic tumor growth, invasion, metastasis, angiogenesis and resistance to apoptosis. This research is of particular importance, as data suggest that a large number of genetic alterations affect only a few major signaling pathways and processes involved in pancreatic tumorigenesis. Although laboratory results of targeted therapies have been impressive, until now only erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated modest survival benefit in combination with gemcitabine in a phase III clinical trial. Whilst the failures of targeted therapies in the clinical setting are discouraging, lessons have been learnt and new therapeutic targets that hold promise for the future management of the disease are continuously emerging. This Review describes some of the important developments and targeted agents for pancreatic cancer that have been tested in clinical trials.

Figure 1

The complex and overlapping pathways and processes involved in pancreatic carcinogenesis. Entities involved in these signal transduction pathways have diverse roles in the promotion of tumor growth, resistance to apoptosis, invasion, metastasis and angiogenesis. Reactivation of physiological, embryonic development pathways is also commonly observed in pancreatic cancer. MMPs are important for tumor invasion and neovascularization. Telomerase is involved in the maintenance of telomeres and is activated in the majority of pancreatic cancers. The miRNAs regulate gene expression post-transcriptionally and can be either oncogenic or tumor-suppressive. Cancer stem cells have been implicated in tumor progression, resistance to chemotherapy and radiotherapy and in disease relapse. Abbreviations: miRNAs, microRNAs; MMP, matrix metalloproteinase.

Figure 2

A simplified representation of oncogenic signaling cascades in pancreatic cancer. a ∣ Binding of ligands to receptors for integrins, VEGF, EGFR, CCK-B/gastrin, HGF and IGF-I activates signaling cascades including the PI3K–Akt and Ras pathways, which affect downstream targets such as NFκB, mTOR and MAPK. FADK binds to integrin receptors and Src to growth factor receptors. FADK–Src interaction increases the activity of FADK. PTEN has the opposite effect to PI3K and inhibits the Akt pathway. Proteasomes degrade IκB, which normally inhibits NFκB. b ∣ Binding of TGF-β forms a complex with TGFBR1 and TGFBR2, which leads to phosphorylation of SMAD2 and SMAD3. These proteins form a complex with SMAD4, which migrates to the nucleus to activate gene transcription. c ∣ The embryonic signaling pathways. Binding of hedgehog proteins to PTC1 releases inhibition of SMO, which leads to activation of downstream targets such as GLI 1. Activation of Notch by its ligands Delta and Jagged leads to its proteolytic cleavage by γ-secretase, and releases the cytoplasmic domain which translocates to the nucleus and binds to transcription factors such as CSL. β-catenin is normally destined for proteasomal degradation. In the canonical Wnt–β-catenin pathway, binding of Wnt proteins stabilizes β-catenin and induces its translocation to the nucleus. β-catenin forms a complex with the TCF–LEF transcription factors to initiate gene expression. Abbreviation: CD, cytoplasmic domain.