Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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The Applicability of mTOR Inhibition in Solid Tumors

Author(s): I.R. H.M. Konings, J. Verweij, E. A.C. Wiemer, S. Sleijfer.

Abstract:

The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin-pathway (PI3K/AKT/mTOR-pathway) plays a role in the regulation of cell proliferation, cell survival, angiogenesis and resistance to anti-tumor treatments. In many tumor types the PI3K/AKT/mTOR-pathway is found activated through several different underlying mechanisms. Since this pathway is believed to largely drive the malignant behavior of several of these tumors, mTOR-inhibition is considered an attractive means to apply as anti-tumor treatment. Currently, four mTOR-inhibitors are explored for clinical use: rapamycin, temsirolimus (CCI-779), everolimus (RAD001) and deforolimus (AP23573). As monotherapy, mTOR-inhibitors yield interesting anti-tumor activity against various tumor types at the expense of relatively mild toxicities. This recently resulted in the registration of two mTOR-inhibitors for patients with metastatic renal cell carcinoma (RCC) while randomized studies in other tumors are currently in progress. Furthermore, mTOR-inhibitors are well-suited drugs to combine with other anti-tumor drugs as in preclinical models mTOR-inhibition overcomes chemoresistance. Consequently, mTOR-inhibitor-containing multidrug regimens are subject to clinical studies. As holds true for all anti-tumor therapies, identification of patients who are likely to respond to mTOR-inhibitorcontaining therapies is of utmost importance to avoid over- or undertreatment. Preliminary results suggest that several factors reflecting activation of mTOR in tumors may be used for this purpose. This review addresses the mechanism of action and current clinical experience with mTOR-inhibitors as well as their role in overcoming resistance to conventional therapies. Additionally, potential predictors of outcome to mTOR-inhibition are discussed.

Keywords: Mammalian target of rapamycin (mTOR), rapamycin, temsirolimus, everolimus, deforolimus, resistance

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Article Details

VOLUME: 9
ISSUE: 3
Year: 2009
Page: [439 - 450]
Pages: 12
DOI: 10.2174/156800909788166556
Price: $58