Inhibition of mTOR in Neuroendocrine Neoplasms of the Digestive Tract

Abstract

The clinical behavior of neuroendocrine neoplasms (NEN) is highly variable. NEN may present as indolent tumors, usually well differentiated, that have limited impact on performance status but are detected at late stages. NEN may also display more aggressive behaviors when cancer cells are poorly differentiated, leading to very rapid tumor growth severely impairing patient general conditions. The term carcinoid was formerly used to identify well-differentiated slowly growing NEN and is actually replaced by the term neuroendocrine tumors G1/G2. Somatostatin analogs have improved the clinical management of patients with NEN by controlling carcinoid symptoms (flushing, diarrhea) and delaying tumor progression. The mammalian target of rapamycin (mTOR), a main protein kinase downstream to the phosphoinositide 3-kinase/Akt signaling pathway, appears as an important intracellular mediator involved in multiple cellular functions including proliferation, differentiation, apoptosis, tumorigenesis, and angiogenesis. Alterations in the normal activity of mTOR and of mTOR-related kinases in this pathway have been found in a diversity of human tumors, including NEN; therefore, mTOR pathway represents an attractive target for new anticancer therapies. While mTOR inhibitors, such as everolimus, are established therapy in pancreatic NET, results from recent clinical trials indicate that mTOR inhibitors may be also of value in the management of non-pancreatic NET. However, ongoing clinical trials will have to confirm efficacy and elucidate, in which subtypes and in which setting these drugs might be most usefully applied.