mTOR Inhibition in Lymphoma: A Rational and Promising Strategy

Since its first description nearly a decade ago, mammalian target of rapamycin (mTOR) has emerged as a critical regulator of cell size and growth in normal and neoplastic conditions. Many cancers rely on mTOR pathway members for their survival, and these proteins thus form attractive targets with wide potential therapeutic indices. Understanding the role of mTOR in lymphomagenesis is complicated by the intricacy of upstream and downstream components as well as potential differences due to the inherent heterogeneity of lymphoma subtypes. Nevertheless, significant data supports a central role of mTOR pathway in lymphoma. Several lymphoma subtypes harbor PTEN deletions, Akt overexpression, or increased eIF4E. Rapamycin is the prototypical mTOR inhibitor, and has clear anti-tumor effects in many lymphoma preclinical models. Newer rapamycin analogs, including the prodrugs temsirolimus and everolimus, and the non prodrug AP23573, are in clinical trials with preliminary, but promising, activity in hematologic malignancies. The limited treatment options for many patients with relapsed lymphomas coupled with the encouraging activity of mTOR inhibitors warrant ongoing attention and clinical development of these agents.