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Profiling mTOR Pathway in Neuroendocrine Tumors

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Management of Neuroendocrine Tumors of the Pancreas and Digestive Tract

Abstract

The serine/threonine kinase mammalian target of rapamycin (mTOR) plays a central role in regulating critical cellular processes such as growth, proliferation, and protein synthesis. The study of cancer predisposing syndromes within which neuroendocrine tumors (NETs) may arise has furnished clues on the involvement of mTOR pathway in sporadic diseases so far. Recent comprehensive analyses have definitely shown activation of mTOR pathway in both experimental and human sporadic NETs. Upstream regulators of mTOR (PTEN and TSC2) have been found mutated in sporadic PNETs. Activation of mTOR pathways in NETs is already demonstrated by expression profiles analysis that revealed downregulation of TSC2 gene and alterations of TSC2 and PTEN protein expression in the vast majority of tumors well-differentiated tumors. Moreover, a global microRNA expression analysis revealed the overexpression, in highly aggressive tumors, of a microRNA (miR-21) that targets PTEN reducing its expression and therefore leading to mTOR activation as well. Overall, these clues have furnished the rationale for the use of mTOR inhibitors the treatment for PNETs. With the recent approval of everolimus (mTOR-targeted drug) for the treatment of advanced PNETs, this paradigm has been effectively translated into the clinical setting. In this review, we discuss mTOR pathway involvement in NETs, the clinical evidence supporting the use of mTOR inhibitors in cancer treatment, and the current clinical issues that remain to be elucidated to improve patients’ management.

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Authors and Affiliations

  1. Medical Oncology, Department of Medicine, University of Verona and Azienda Ospedaliera Universitaria Integrata, P.le Scuro 10, 37134, Verona, Italy

    S. Cingarlini, M. Bonomi, C. Trentin & G. Tortora

  2. ARC-NET Research Centre and Department of Pathology and Diagnostics, University of Verona and Azienda Ospedaliera Universitaria Integrata, Verona, Italy

    V. Corbo & A. Scarpa

Authors
  1. S. Cingarlini
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  2. M. Bonomi
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  3. C. Trentin
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  4. V. Corbo
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  5. A. Scarpa
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  6. G. Tortora
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Correspondence to G. Tortora .

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Editors and Affiliations

  1. Medical Oncology, Bichat-Beaujon University Hospitals, Clichy cedex, France

    Eric Raymond

  2. Bichat-Beaujon University Hospitals Medical Oncology, Clichy cedex, France

    Sandrine Faivre

  3. Pancreatology, Bichat-Beaujon University Hospitals Gastroenterology and, Clichy cedex, France

    Philippe Ruszniewski

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Cingarlini, S., Bonomi, M., Trentin, C., Corbo, V., Scarpa, A., Tortora, G. (2014). Profiling mTOR Pathway in Neuroendocrine Tumors. In: Raymond, E., Faivre, S., Ruszniewski, P. (eds) Management of Neuroendocrine Tumors of the Pancreas and Digestive Tract. Springer, Paris. https://doi.org/10.1007/978-2-8178-0430-9_2

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  • DOI: https://doi.org/10.1007/978-2-8178-0430-9_2

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