Title:Target Therapies in Pancreatic Carcinoma
Volume: 21
Issue: 8
Author(s): Nicola Silvestris, Antonio Gnoni, Anna Elisabetta Brunetti, Leonardo Vincenti, Daniele Santini, Giuseppe Tonini, Francesca Merchionne, Evaristo Maiello, Vito Lorusso, Patrizia Nardulli, Amalia Azzariti and Michele Reni
Affiliation:
Keywords:
bevacizumab, epidermal growth factor receptor (EGFR) inhibitors, erlotinib, hedgehog inhibitors, insuline-growth
factor receptor (IGF-1R) inhibitors, metalloproteinases, nab-paclitaxel, pancreatic ductal adenocarcinoma, radiotherapy, targeted
therapy, vascular endothelial growth factor (VEGF).
Abstract: Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early locoregional spread and
distant metastases at diagnosis, leading to dismal prognosis and limited treatment options. Traditional cytotoxic chemotherapy
provides only modest benefit to patients with PDAC. Identification of different molecular pathways, overexpressed
in pancreatic cancer cells, has provided the opportunity to develop targeted therapies (monoclonal antibodies and
small-molecule inhibitors) and peculiar new class of taxanes with a crucial therapeutic role in this cancer setting. A phase
III trial has shown that erlotinib in combination with gemcitabine was clinically irrelevant and skin toxicity can be a positive
prognostic factor. Moreover, the combination of cetuximab or erlotinib with radiotherapy in advanced pancreatic cancer
has shown to be synergistic and a reversal of radio-resistance has been suggested by inhibition of VEGF/EGFR pathway.
To overcome EGFR-inhibition therapy resistance several alternative pathways targets are under investigation (IGF-
1R, MMPs, Hedgehog proteins, m-TOR, MEK, COX-2) and provide the rationale for clinical use in phase II/III studies.
Also nab-paclitaxel, a new taxanes class, uses high pancreatic albumin-binding protein SPARC levels to act in cancer
cells with a less toxic and more effective dose with respect to classic taxanes. Understanding of molecular pathogenesis of
pancreatic adenocarcinoma continues to expand. However, many promising data in preclinic and phase I/II trials did not
yield promise in phase III trials, suggesting that identification of predictive biomarkers for these new agents is mandatory.
The knowledge of biologic and molecular aspects of pancreatic cancer can be the basis for future therapeutic developments.
