The Role of Mammalian Target of Rapamycin (mTOR) Inhibitors in the Treatment of Solid Tumors

Arun      Rajan; Ajeet      Gajra

Abstract

Mammalian target of rapamycin (mTOR) is a cytoplasmic kinase that is a downstream component of the phosphatidylinositol 3-kinase (PI3K)/Akt kinase cascade. Together with its associated proteins, it can affect mRNA transcription, protein translation, protein degradation and changes in the actin cytoskeleton. Since mTOR has the ability to influence cell proliferation and apoptosis, it plays an important role in carcinogenesis. The existence of specific inhibitors of mTOR in the form of the antibiotic rapamycin, and its analogs, make the mTOR signaling pathway an attractive target for anti-cancer therapy. Rapamycin (sirolimus, Wyeth Pharmaceuticals, Philadelphia, PA) is a macrocyclic lactone that forms a complex with the intracellular immunophilin FKBP12 and inhibits mTOR. Rapamycin derivatives that are being evaluated in clinical trials include CCI-779 (temsirolimus), RAD001 (everolimus) and AP23573. Rapamycin inhibits T-cell proliferation and is thus used as an immunosuppressive agent. Temsirolimus (Wyeth Pharmaceuticals, Philadelphia, PA) has been evaluated in renal cell carcinoma (RCC), endometrial carcinoma, glioblastoma, breast cancer and mantle cell lymphoma. Everolimus (Novartis, East Hanover, NJ) is a macrolide derivative of rapamycin that has been evaluated in patients with imatinibrefractory gastrointestinal stromal tumors. AP23573 (ARIAD Pharmaceuticals, Cambridge, MA) is an intravenous (iv) mTOR inhibitor that has demonstrated antitumor activity against sarcomas. These examples illustrate the fact that mTOR inhibition is a viable therapeutic option in the treatment of solid tumors and further development of this new class of antineoplastic drugs should be pursued.

Keywords: Solid Tumors, Mammalian Target of Rapamycin (mTOR), carcinogenesis, apoptosis, cell proliferation, antibiotic rapamycin, anti-cancer therapy, immunosuppressive agent