Updating progress in sarcoma therapy with mTOR inhibitors

Abstract

Background: Sarcomas are a diverse group of difficult-to-treat connective tissue neoplasms. The mammalian target of rapamycin (mTOR) pathway has been identified as a therapeutic target in many sarcomas and this article reviews the role of this pathway and updates clinical data for the available mTOR inhibitors.Design: Reference sources were selected by the author for searches in PubMed and EMBASE, with search terms dependent on the particular subtopic. Results: mTOR is a protein kinase that regulates cell growth and proliferation and is abnormally activated in many human tumours. Several disruptions of phosphatidylinositol-3′ kinase (PI3K)-Akt signalling are associated with different sarcoma types. The macrolide antibiotic rapamycin and synthetic derivatives sirolimus, temsirolimus, everolimus and ridaforolimus have been investigated in several tumour types and their potential for the treatment of sarcoma is being explored, with varying degrees of success. The PI3K-Akt-mTOR pathway is also implicated in resistance mechanisms to antineoplastic therapies, and mTOR inhibitors therefore have the potential to restore sensitivity to patients with treatment-resistant disease. Conclusions: The PI3K-Akt-mTOR pathway is an exciting target for therapy in many types of solid malignancies and its blockade represents an opportunity to improve outcomes in poor-prognosis sarcoma. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.