Translation of molecular pathways into clinical trials of neuroendocrine tumors.

Current treatment options for neuroendocrine tumors (NET) include somatostatin analogs, interferon-α, peptide receptor-targeted therapy and cytotoxic chemotherapy. Most patients undergo sequential therapies since these drugs are active only in subpopulations of patients and for a limited period of time. There is a need for novel drugs that are capable of amelioration of symptomatology (syndromic control) and/or tumor growth control. A number of diverse signaling pathways are involved in the pathogenesis of NET and tumor growth, thus many potential targets are available for drug targeting. Targeted therapies therefore represent an appropriate developmental therapeutic strategy given the multiplicity of potential targets in NET. These include but are not limited to: inhibitory or activating G protein-coupled receptors, receptor tyrosine kinases, ligands, and intracellular targets such as the mammalian target of rapamycin (mTOR). Numerous drugs that utilize single or multiple targets are currently in clinical development. Recently, two target-directed agents, the multiple tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus, have been approved for the treatment of progressive pancreatic NET. This review provides a broad overview of established and potential molecular targets in NET, summarizes data from phase II and III clinical trials with targeted drugs and outlines future therapeutic directions.