Emerging roles for mammalian target of rapamycin inhibitors in the treatment of solid tumors and hematological malignancies.

PURPOSE OF REVIEW: The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and survival in mammalian cells. mTOR pathways are frequently dysregulated in various malignancies, providing targets for new anticancer drugs and therapeutic strategies. Here, we summarize the clinical experience of trials using the first generation of mTOR inhibitors, the rapalogs, and highlight the development of the next generation of catalytic inhibitors of the pathway.

RECENT FINDINGS: mTOR inhibitors have shown major clinical activity in the treatment of renal cell carcinoma and two rapalogs have been approved for treatment of this malignancy. Recently, clinically significant trials with these agents were conducted in mantle cell lymphoma, pancreatic neuroendocrine tumors and astrocytomas. There are also promising results emerging in sarcomas, breast cancer and lung carcinoma. Multiple agents targeting mTOR, belonging to the new class of catalytic inhibitors with activity against both mTORC1 and mTORC2, are currently in various stages of preclinical and clinical development.

SUMMARY: The rapalogs are the first mTOR inhibitors to show promising, yet modest, antitumor effects. To fully exploit the potential of targeting this pathway, it will be important to better understand the mechanisms of action and precise targets of the various inhibitors. Moreover, definition of biomarkers of susceptibility and identification of predictors and/or correlates to drug resistance will substantially advance this area.