From targets to treatments: a review of molecular targets in pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (pancreatic NET) are relatively rare, slowly growing tumors, although their incidence is increasing, and patients may survive for several years with metastatic disease. Apart from symptomatic relief, there have been few treatment options for these tumors in the past. More recently, investigators have explored the potential of molecularly targeted agents in treating pancreatic NET, with some success. In this review, we consider the data supporting exploitation of different targets in pancreatic NET, including peptide receptors, receptor tyrosine kinases (involved in tumor angiogenesis and more directly supporting tumor growth), and intracellular targets, such as the mammalian target of rapamycin (mTOR), which has a central role in regulating cell growth, metabolism, and apoptosis. Probably due to the paucity of pancreatic NET, many clinical trials to date have included heterogeneous NET populations, and there are few randomized studies of this specific patient population. Very recently, promising results have been achieved in placebo-controlled, phase III trials with the multitargeted tyrosine kinase inhibitor, sunitinib, and the mTOR inhibitor, everolimus. These agents have been approved or are currently being reviewed by authorities for use in patients with pancreatic NET. Here we review potential molecular targets in pancreatic NET and summarize the available data for targeted agents from phase II and III trials open to patients with this tumor.