Growth factor receptors as targets for novel treatment strategies of neuroendocrine tumors

Both the epidermal growth factor receptor (EGFR) and the insulin-like growth factor receptor (IGFR) are commonly (over-)expressed in many cancers including neuroendocrine tumors (NETs); clinical trials indicate that these antigens have important roles in cancer etiology and progression. EGFR and IGFR thus provide rational targets for cancer therapies and a number of strategies influencing these receptors, and its downstream signal cascades, including monoclonal antibodies, tyrosine-kinase inhibitors or antisense oligonucleotides have been evaluated. In particular, monoclonal antibodies targeting the receptors' extracellular domains and small molecules blocking (tyrosine-) kinase activation intracellularly have already shown activity in clinical phase II trials of neuroendocrine tumors. The clinically well established somatostatin analogues are known to inhibit both insulin-like growth factor (IGF1) and vascular endothelial growth factor (VEGF) production in NETs. As generally neuroendocrine tumors and their metastases represent hypervascularized neoplasms, inhibition of VEGF or VEGF receptor (VEGFR)-tyrosine kinases (VEGFR-TK) is a rational approach to go for. Phase II studies have indeed provided evidence for the antineoplastic potency of VEGF or VEGFR-TK inhibition by either monoclonal antibodies, tyrosine kinase blockers or thalidomide in NETs. Some small molecules not only inhibit VEGFR but also EGFR or platelet derived growth factor receptor (PDGFR)-tyrosine kinases or c-KIT; several of these molecules have successfully been tested for their antiproliferative effects in NETs. The serine-threonine kinase mTOR is linked to several growth factor receptors including EGFR and IGFR. mTOR plays an important role in cell growth and cancer proliferation. Recently, everolimus, a macrolide mTOR inhibitor, has been combined with the somatostatin analogue octreotide for effective growth control of NET disease in a phase II study. However, many questions remain unanswered and future issues in the development of EGFR, IGF(R) or VEGF(R) inhibitors will include the identification of biological predictors of response, combination with other therapies and also their use in earlier stages of NET disease. In ongoing clinical trials EGFR and/or VEGF/VEGFR blockade or mTOR inhibitors are combined with either cytostatics or stable somatostatin analogues. In summary, growth factor receptors and their downstream signal cascades are very promising targets for novel treatment strategies of NETs.