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Overview and mechanism of action of mTOR inhibitors

    Stéphane Oudard

    Stéphane Oudard is Professor of Oncology and Chief of the Oncology Clinical and Translational Research Unit at the Georges Pompidou Hospital in Paris, France. He received his medical degree from Hôlactone produced by the fungustel-Dieu Hospital, University of Paris, France (1993). On completion of his residency in medical oncology in Paris, he obtained his Masters of Science at Lariboisière-Saint Louis University Hospital, Paris, France (1994) and his Doctorate at Institut Curie, Paris, France (1996). He completed a 2-year fellowship in cancer research at Georgetown University, Washington, DC, USA, before returning to Paris. He has authored more than 125 scientific articles and 30 literature reviews that have been published in various international journals. He is currently a member of the French Cancer Society, European Society for Medical Oncology and the American Society of Clinical Oncology. As a clinical researcher, he has served as a coordinator, investigator, or coinvestigator on several Phase I-III French, European and international clinical trials. He has been largely involved in the development of cabazitaxel, sorafenib, sunitinib and everolimus for treatment of uro–oncology tumors. His research interests include prostate and kidney cancers, translational research, angiogenesis, inhibition of glycolysis and drug resistance. He is the principal investigator (PI) of the Rising PSA Phase III trial and french PI of the PREDICT trial.

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    Published Online:8 Dec 2011https://doi.org/10.2217/ebo.11.208
    Abstract:

    Over recent years, much work on the treatment of solid tumors has focused on the search for inhibitors that reduce tumor vascularity by inhibition of angiogenesis, in view of the well-established role of angiogenesis in the maintenance of solid tumor growth. The first types of angiogenesis inhibitor to be introduced were inhibitors of the tyrosine kinase activity of several growth factor receptors present on the surface of endothelial cells, in particular, the VEGF and PDGF receptor. Examples of tyrosine kinase activity inhibiting VEGF receptors and other growth factor receptors are sorafenib, sunitinib, pazopanib and axitinib [1–4]. Another strategy has been to develop monoclonal antibodies directed against circulating VEGF, namely bevacizumab [5]. Inhibitors that have been more recently developed, however, target the mTOR pathway. mTOR is a serine/threonine kinase discovered empirically during studies on rapamycin (sirolimus). Rapamycin is a macrocyclic lactone produced by the fungus Streptomyces hygroscopicus and has immunosuppressive, antimicrobial and antitumor properties. mTOR has a central regulatory function in the synthesis of key cellular proteins that influence several aspects of cell growth, differentiation, cell cycle progression,angiogenesis, protein degradation and apoptosis [6].It is a downstream effector of the PI3K pathway, known to be dysregulated in a wide range of malignancies, and has thus become an attractive target for inhibition of cell growth, proliferation and angiogenesis. This overview will briefly describe the PI3K/Akt/mTOR pathway; highlight some of the defects in solid tumors that have been linked with dysregulation of this pathway; explain the mechanism of action of mTOR inhibitors; describe approved mTOR inhibitors and their indications; and hint at future directions.

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