A better understanding of the mechanisms driving secretion and tumour growth has led to the development of several targeted antitumour agents in these rare tumours. NETs express a variety of peptide receptors including somatostatin receptors (sstr) and express interferon (IFN) receptors. Inhibition of sstr and IFN signalling by somatostatin analogues and interferon-alpha is an established approach to control secretion and growth of NET. Introduced in the mid 1980s, both drug classes can be considered as the oldest targeted drugs in the management of NET (see Chaps. 28, 29, 30).

Several growth-promoting targets are expressed in NET cells [3, 4]. These comprise not only growth factor receptors but also their ligands or other molecules, including vascular endothelial growth factor (VEGF), platelet-derived growth factor-α (PDGFR-α), platelet-derived growth factor-ß (PDGFR-ß), insulin-like growth factor 1 (IGF-1), transforming growth factor-α (TGF-α) and TGF-ß, and their cognate receptors [5]. VEGF-driven angiogenesis may play an important role in neuroendocrine tumorigenesis and tumour progression [6]. High vascularity is however rather a feature of well-differentiated than poorly differentiated NET. The epidermal growth factor (EGF) receptor is frequently expressed in NET, and binding of EGF or TGF-α induces RAF/MAP-ERK signalling in tumour cells; however, mutations of the EGFR tyrosine kinase which are predictive of a response to EGFR tyrosine kinase inhibitors in other types of cancers are rather uncommon in NET [7]. Activation of the IGF-1R by IGF-1 and IGF-2 plays an important role in tumour cell proliferation, and in NET cell lines (pancreatic BON cells), it has been demonstrated that IGF-1 stimulates tumour cell growth by an autocrine loop. IGF-1 also plays a role in the upstream activation of the mammalian target of rapamycin (mTOR) pathway [8, 9].

The protein kinase mTOR exerts a central control function integrating multiple signalling pathways in response to growth factors and intracellular signalling by nutrients. mTOR is involved in the regulation of growth-related cellular functions, and the best known function is the regulation of translation initiation [10]. Inhibiting mTOR pathway may reduce cell growth and proliferation and impair the metastatic potential of tumour cells. It also acts at the endothelial cells. In NET constitutively activated PI3K-Akt-mTOR signalling seems to be a crucial event with 75 % of NET expressing activated Akt and 45 % mTOR [11]. Loss or downregulation of the expression of PTEN or TSC2 has been reported recently in a high percentage of pancreatic NET and may lead by loss of inhibition of mTOR to overactivation of this pathway [12].

In NETs, mTOR inhibitors and angiogenesis inhibitors have been most extensively studied. The following sections focus on the results from clinical trials with both kinds of drugs.