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.
Everolimus, an oral mammalian target of rapamycin(mTOR) inhibitor, which acts upstream of the phosphoinositide 3-kinase/protein kinase B(PI3K/AKT) signaling pathway to downregulate cellular metabolism, growth, proliferation, and angiogenesis, has been shown to significantly prolong the progression-free survival of patients with advanced neuroendocrine tumors.
The prevalence of these potential prognostic biomarkers in early disease was observed in 3.3% of the primary tumor cohort. mTOR pathway variants including alterations in PTEN, TSC2 and PIK3CA were identified in 10% and 12.5% of primary tumors and pNET liver metastasis, respectively.
The significant progress in molecular biology shed light on the significant role of PI3K/Akt/mTOR pathway and angiogenesis in NETs, while the success of everolimus and sunitinib in landmark clinical trials opened new avenues in the discovery of effective treatments.
Neuroendocrine cancer cell lines are used to investigate therapeutic targets in neuroendocrine tumors (NET) and have been instrumental in the design of clinical trials targeting the PI3K/AKT/mTOR pathways, VEGF inhibitors, and somatostatin analogues.
While alterations in the chromatin remodeling and PI3K/Akt/mTOR pathways are present in most well-differentiated pancreatic neuroendocrine tumors, mutations in TP53 and RB may contribute to the development of pancreatic poorly differentiated neuroendocrine carcinomas.
Several inhibitors of the phosphoinositide 3-kinase (PI(3)K)-Akt-mTOR signaling pathway are currently being evaluated in clinical phase II and III studies for the treatment of NETs with promising results.
Our results strongly support a role for PI3K/Akt/mTOR pathway in PET, which ties in with the fact that mTOR inhibitors have reached phase III trials in neuroendocrine tumors.