Clinical Development of mTOR Inhibitors: A Focus on Lymphoma

Sonali   M.   Smith

Abstract

The mammalian target of rapamycin (mTOR) kinase is positioned at the juncture of several pathways regulating cell growth and proliferation. It is the downstream effector of the oncogenic PI3K/Akt pathway and is a key regulator of translational initiation. Accumulating data support mTORs role in lymphomagenesis, and its inhibition in preclinical models leads to lymphoma regression. The rationale for testing mTOR inhibitors in patients with lymphoma is evident, and early clinical data is promising. Along with the prototype of mTOR inhibitors, rapamycin, there are three mTOR inhibitors furthest along in development: temsirolimus, everolimus, and AP23573. These agents are emerging as well-tolerated drugs with encouraging preliminary activity. Here we review the rationale for testing mTOR inhibitors in lymphoma, the phase 1 trials influencing dose and schedule of mTOR inhibitors, and summarize the clinical results in obtained to date in patients with lymphoma.

Keywords: mTOR, mTOR inhibitors, non-Hodgkin lymphoma, rapamycin, clinical trials, pharmacokinetics