Will mTOR inhibitors make it as cancer drugs?

Abstract

Main Text Introduction Several pharmaceutical and biotechnology companies are actively pursuing the clinical development of inhibitors of the serine/threonine kinase mammalian target of rapamycin (mTOR) for cancer. Rapamycin, the original natural product compound first shown to inhibit mTOR, is already an approved drug for prevention of allograft rejection in recipients of organ transplants due to its potent inhibition of T cell activation. What is the logic behind the use of the same agent for cancer indications? This focus will review the background supporting the potential utility of mTOR inhibitors as anticancer agents, then compare and contrast two different approaches for its clinical development. The first approach is empiric, based on the traditional phase I design of escalation to maximum tolerated dose in a broad patient population, followed by larger trials focused on those tumor types that demonstrate hints of activity in the phase I setting. The second approach is mechanism based, building on knowledge of signaling pathways that activate mTOR, where the dose is selected by measuring target enzyme inhibition in tumor cells and patient eligibility is defined by molecular profiling studies. I will speculate on potential outcomes from both approaches as well as my view of the eventual role that mTOR inhibitors may play in the cancer drug armamentarium. mTOR: A central regulator of cell growth Rapamycin, a bacterially derived natural product, induces G1 arrest in various cell types at low nanomolar concentrations. The mechanism was cleverly deciphered through yeast genetic screens that identified a serine/threonine kinase named target of rapamycin (TOR) ( Heitman et al. 1991 Heitman J. Movva N.R. Hall M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. 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