Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets

Abstract

Molecular targeted therapy of advanced neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) system currently encompasses approved therapy with the mammalian target of rapamycin (mTOR) inhibitor everolimus and the multi-tyrosinkinase inhibitor sunitinib. However, clinical efficacy of these treatment strategies is limited by low objective response rates and limited progression-free survival due to tumour resistance. Further novel strategies for molecular targeted therapy of NETs of the GEP system are needed. This paper reviews preclinical research models and signalling pathways in NETs of the GEP system. Preclinical and early clinical data on putative novel targets for molecular targeted therapy of NETs of the GEP system are discussed, including PI3K, Akt, mTORC1/mTORC2, GSK3, c-Met, Ras-Raf-MEK-ERK, embryogenic pathways (Hedgehog, Notch, Wnt/beta-catenin, TGF-beta signalling and SMAD proteins), tumour suppressors and cell cycle regulators (p53, cyclin-dependent kinases (CDKs) CDK4/6, CDK inhibitor p27, retinoblastoma protein (Rb)), heat shock protein HSP90, Aurora kinase, Src kinase family, focal adhesion kinase and epigenetic modulation by histone deacetylase inhibitors.

Keywords: neuroendocrine tumours; targeted therapy.

Figure 1

Important growth factors and cellular signalling pathways involved in tumourigenesis and angiogenesis of NETs. PI3K–Akt–mTOR pathway, Ras–Raf–MEK–ERK pathway, Wnt/beta-catenin pathway, Notch-1 signalling and Hedgehog signalling, cyclin-dependent kinases in a cellular context.