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Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors.

ABSTRACT: : The carcinoid syndrome represents a set of signs and symptoms associated with neuroendocrine tumors (NETs) that occur primarily when metastases are developed in the liver, resulting in the worsening of quality of life. Serotonin plays a central role in the physiology of carcinoid syndrome by promoting intestinal motility. Somatostatin analogs (SSAs) have widely demonstrated their efficacy as symptomatic relievers of carcinoid syndrome, but this control is ephemeral, being reduced by approximately 50% within the first year. The exact mechanisms of resistance to SSAs are not fully understood, but it is believed that serotonin might be involved. Patients with carcinoid syndrome present with a significant increase in serotonin plasma levels and, consequently, in the soluble urinary metabolite 5-hydroxyindole acetic acid. Telotristat etiprate is a potent inhibitor of tryptophan hydroxylase, a rate-limiting enzyme in the synthesis of serotonin, that has demonstrated in the phase III TELESTAR clinical trial a significant improvement in the control of bowel movements in patients with NETs who have carcinoid syndrome and who have progressed to an SSA. Based on these results, telotristat etiprate has emerged as a potential new option in the treatment algorithm of symptomatic control of functioning NETs. However, some issues need to be clarified, such as the safety profile of the drug outside clinical trials, the benefit in quality of life, and the possible impact on tumor growth, as well as its role within sequencing or combination treatment strategies with pre-existing drugs effective in NET treatment.This article reviews the literature about carcinoid syndrome, which affects patients diagnosed with neuroendocrine tumors. Few articles have been published about this syndrome and its pathophysiology. Somatostatin analogs provide symptomatic relief; however, patients may become refractory to this strategy, usually within the first year of treatment. In this context, as an agent with an innovative mechanism of action, telotristat etiprate has demonstrated activity in a phase III trial, and findings may offer a path to an improve quality of life and prolonged survival for certain patients.

SUBMITTER: Molina-Cerrillo J

PROVIDER: S-EPMC4912367 | biostudies-other | 2016 Jun

REPOSITORIES: biostudies-other

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Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors.

Molina-Cerrillo Javier J Alonso-Gordoa Teresa T Martínez-Sáez Olga O Grande Enrique E

The oncologist 20160422 6

<h4>Unlabelled</h4>: The carcinoid syndrome represents a set of signs and symptoms associated with neuroendocrine tumors (NETs) that occur primarily when metastases are developed in the liver, resulting in the worsening of quality of life. Serotonin plays a central role in the physiology of carcinoid syndrome by promoting intestinal motility. Somatostatin analogs (SSAs) have widely demonstrated their efficacy as symptomatic relievers of carcinoid syndrome, but this control is ephemeral, being re ...[more]

PMID: 27107003

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Project description:Essentials Tissue factor (TF) isoforms are expressed in pancreatic neuroendocrine tumors (pNET). TF knockdown inhibits proliferation of human pNET cells in vitro. mTOR kinase inhibitor sapanisertib/MLN0128 suppresses TF expression in human pNET cells. Sapanisertib suppresses TF expression and activity and reduces the growth of pNET tumors in vivo. SUMMARY: Background Full-length tissue factor (flTF) and alternatively spliced TF (asTF) contribute to growth and spread of pancreatic ductal adenocarcinoma. It is unknown, however, if flTF and/or asTF contribute to the pathobiology of pancreatic neuroendocrine tumors (pNETs). Objective To assess TF expression in pNETs and the effects of mTOR complex 1/2 (mTORC1/2) inhibition on pNET growth. Methods Human pNET specimens were immunostained for TF. Human pNET cell lines QGP1 and BON were evaluated for TF expression and responsiveness to mTOR inhibition. shRNA were used to knock down TF in BON. TF cofactor activity was assessed using a two-step FXa generation assay. TF promoter activity was assessed using transient transfection of human TF promoter-driven reporter constructs into cells. Mice bearing orthotopic BON tumors were treated with the mTORC1/2 ATP site competitive inhibitor sapanisertib/MLN0128 (3 mg kg-1 , oral gavage) for 34 days. Results Immunostaining of pNET tissue revealed flTF and asTF expression. BON and QGP1 expressed both TF isoforms, with BON exhibiting higher levels. shRNA directed against TF suppressed BON proliferation in vitro. Treatment of BON with sapanisertib inhibited mTOR signaling and suppressed TF levels. BON tumors grown in mice treated with sapanisertib had significantly less TF protein and cofactor activity, and were smaller compared with tumors grown in control mice. Conclusions TF isoforms are expressed in pNETs. Sapanisertib suppresses TF mRNA and protein expression as well as TF cofactor activity in vitro and in vivo. Thus, further studies are warranted to evaluate the clinical utility of TF-suppressing mTORC1/2 inhibitor sapanisertib in pNET management.

Dataset Information

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors.

Publications

Inhibition of Peripheral Synthesis of Serotonin as a New Target in Neuroendocrine Tumors.

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