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Pancreatic Cancer Treatments: The Promise of Signal Transduction Pathways

Contributed by Jill R. Glausier, Ph.D.

Successfully treating pancreatic cancer represents one of the biggest challenges in oncology to date. Pancreatic cancer has the lowest five-year survival rate of all cancers1; equivalent incidence and mortality rates2; and an underwhelming response to all widely available treatments, including surgical resection3,4. The poor prognosis of pancreatic cancer highlights the need to identify additional therapeutic targets in order to produce more efficacious therapies. To this end, signal transduction cascades associated with pancreatic cancer cells are an area of intense research that has much promise5,6.

Detection of MafA in FFPE mouse pancreatic islet.

Detection of MafA in FFPE mouse pancreatic islet. Antibody: Rabbit anti-MafA (IHC-00352). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Signal transduction pathways include both the membrane-bound receptor that receives the signal, and the complex molecular pathway which then transduces the signal into intracellular activity. Alterations to epidermal growth factor receptors (EGFR) and several molecules within two EGFR-initiated signal transduction pathways are heavily implicated in pancreatic cancer5,7,8. EGFR is overexpressed in the majority of pancreatic cancers9,10, and this excessive expression is associated with an even worse prognosis for the individual11,12. Interestingly, EGFR inhibitors have shown only modest clinical benefits7,13,14, and this may be due to the concomitant mutations and alterations to EGFR signal transduction molecules. For example, one key EGFR-initiated pathway includes K-Ras/RAF/MEK/ERK/MAP2K. Single point mutations in the K-Ras gene have been identified in pancreatic cancers, causing constitutive activation and initiation of various cellular processes that contribute to tumorogenesis5,15-17. The PI3K/AKT/mTOR pathway is another EGFR signal transduction cascade implicated in pancreatic cancer5,6,18. This pathway is involved with the enhancement of cell growth and survival, and also appears to be excessively activated in pancreatic cancers19,20. Numerous other signal transduction molecules and pathways are implicated in pancreatic cancer cells and the stroma, including: 1) JAK/STAT, 2) cyclooxygenase-2 (COX-2), 3) sonic hedgehog (SHH), 4) Notch, and 5) WNT. For example, many pancreatic cancers are associated with persistently active STAT321,22, and excessive COX-2 and WNT expression23,24.

The abundance of signaling pathways implicated in pancreatic cancer etiology and progression provides a wealth of possible therapeutic targets that may apply to all, or to subpopulations, of patients. This characteristic of pancreatic cancer may position it as an ideal model for the refinement and application of personalized medicine25,26.

 

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