Epigenetic aspects on therapy development for gastroenteropancreatic neuroendocrine tumors.

The understanding of epigenetic modifications in gastroenteropancreatic neuroendocrine tumors is a novel and still small field. Activation of the insulin-like growth factor 2 gene locus by loss of imprinting is a classical epigenetic alteration frequently observed in insulinoma. Inactivation of the MEN1 gene, commonly involved in endocrine pancreatic tumors, impairs the association with mixed lineage leukemia involved in histone H3K4me3 methylation. In addition, promising effects on tumor phenotypes such as growth, apoptosis, cell cycle arrest, and expression of neuroendocrine markers have been obtained in vitro for inhibitors of DNA methyltransferase (azacytidine) and histone deacetylation (butyrate, valproic acid, trichostatin A and MS-275). The frequent need for complementary treatments in addition to surgery in this tumor entity supports further efforts in the development and application of drugs acting at general as well as more specific epigenetic alterations.