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Signaling mechanisms in neuroendocrine tumors as targets for therapy.

ABSTRACT: Although neuroendocrine tumors are rare, the more common types such as gastrointestinal and pancreatic carcinoids, medullary thyroid cancers, and small cell lung cancers have been studied in detail during the last few years. Data published thus far indicate that multiple signaling pathways are involved in these cancers. Recent focus has been on developing novel therapeutics by targeting specific signaling pathways. This article details several of the signaling mechanisms that have been discovered to play a role in the development and progression of neuroendocrine tumors. The therapeutic options developed to address the various pathways, including their specific mechanisms of actions, are also discussed.

SUBMITTER: Zarebczan B

PROVIDER: S-EPMC3011942 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other

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Signaling mechanisms in neuroendocrine tumors as targets for therapy.

Zarebczan Barbara B Chen Herbert H

Endocrinology and metabolism clinics of North America 20101201 4

Although neuroendocrine tumors are rare, the more common types such as gastrointestinal and pancreatic carcinoids, medullary thyroid cancers, and small cell lung cancers have been studied in detail during the last few years. Data published thus far indicate that multiple signaling pathways are involved in these cancers. Recent focus has been on developing novel therapeutics by targeting specific signaling pathways. This article details several of the signaling mechanisms that have been discovere ...[more]

PMID: 21095546

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Project description:Opinion statementNeuroendocrine tumors (NETs) are a heterogeneous group of malignancies characterized by variable but most often indolent biologic behavior. Well-differentiated NETs can be broadly classified as either carcinoid or pancreatic NET. Although they have similar characteristics on routine histologic evaluation, the 2 tumor subtypes have different biology and respond differently to treatment, with most therapeutic agents demonstrating higher response rates in pancreatic NETs compared with carcinoid. Until recently, systemic treatment options for patients with advanced NETs were limited. However, improvements in our understanding of signaling pathways involved in the pathogenesis, growth, and spread of NETs have translated into an expansion of treatment options. Aberrant signaling through the mechanistic pathway of rapamycin (mTOR) pathway has been implicated in neuroendocrine tumorigenesis. Additionally, altered expression of mTOR pathway components has been observed in NETs and has been associated with clinical outcomes. Targeting the mTOR pathway has emerged as an effective treatment strategy in the management of advanced NETs. In a randomized, placebo-controlled study of patients with advanced pancreatic NET, treatment with the mTOR inhibitor everolimus was associated with improved progression-free survival (PFS). Largely based upon these data, everolimus has been approved in the United States and Europe for the treatment of patients with advanced pancreatic NET. The activity of everolimus remains under investigation in patients with carcinoid tumors. In a randomized study of patients with advanced carcinoid tumors associated with carcinoid syndrome, the addition of everolimus to octreotide was associated with improved PFS compared with octreotide. However, the results did not meet the prespecified level of statistical significance based on central review of radiographic imaging. Results from a randomized study examining the efficacy of everolimus in patients with nonfunctional gastrointestinal and lung NETs are awaited. In addition, further investigation is needed to determine whether primary tumor site or other clinical and molecular factors can impact response to mTOR inhibition. Although everolimus can slow tumor progression, significant tumor reduction is rarely obtained. Targeting multiple signaling pathways is a treatment strategy that may provide better tumor control and overcome resistance mechanisms involved with targeting a single pathway. Results of ongoing and future studies will provide important information regarding the added benefit of combining mTOR inhibitors with other targeted agents, such as VEGF pathway inhibitors, and cytotoxic chemotherapy in the treatment of advanced NETs.

Dataset Information

Signaling mechanisms in neuroendocrine tumors as targets for therapy.

Publications

Signaling mechanisms in neuroendocrine tumors as targets for therapy.

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