Rapamycin Analogs

Rapamycin and its analogs, known as rapalogs, are the first generation of mTOR inhibitors, sharing the same molecular scaffold but differing in physiochemical properties. ^[1] Everolimus is an oral protein kinase inhibitor of the mammalian target of rapamycin (mTOR) serine/threonine kinase signal transduction pathway. ^{[2] [3]} Temsirolimus (CCI-779) is a water-soluble synthetic rapamycin ester and small-molecule inhibitor of mTOR protein developed in oral and intravenous formulations. ^{[4] [5]} Among the rapalogs, temsirolimus and everolimus have been approved for the treatment of breast and renal cancer. ^[1]

The PI3K/AKT/mTOR pathway is a signaling pathway involved in cell proliferation, survival, growth, metabolism and other fundamental processes, and is frequently deregulated in cancer. ^{[6] [3]} Inhibition of mTOR protein abrogates pathway-mediated cellular transcription and translation, leading to cell cycle arrest, antiangiogenesis and apoptosis. ^{[4] [5]} Everolimus and temsirolimus inhibit mechanistic target of rapamycin complex 1 (mTORC1). ^[7]

Inhibitors of mTOR have been approved for the treatment of renal cell carcinoma and appear to have a role in the treatment of other malignancies. ^[8] Everolimus, an orally administered rapamycin analog, was approved by the US FDA for treatment of renal cell carcinoma refractory to VEGF receptor signaling inhibitors, where it significantly increased median progression-free survival to 4.0 months versus 1.9 months for placebo. ^[9] In a large phase III study, patients with advanced renal cell carcinoma and poor prognosis given once-weekly intravenous temsirolimus achieved median overall survival of 10.9 versus 7.3 months compared with interferon-alpha therapy. ^{[5] [10]} Everolimus, a rapamycin-derived mTOR inhibitor, reduces seizure frequency in tuberous sclerosis complex and is FDA approved for anti-seizure therapy in that condition. ^{[11] [12]}

As immunosuppressants, the mTOR inhibitors sirolimus and everolimus can cause side effects such as hypertension, infection, and hyperlipidemia. ^[14] Notable temsirolimus-related toxicities include rash, mucostomatitis, diarrhea, hyperlipidemia, hyperglycemia and thrombocytopenia, with frequency and intensity increasing at higher doses. ^[4] Treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia and new-onset diabetes, ranging from 13% to 50% in clinical trials where they were used as anticancer therapies, so close personalized follow-up of blood glucose is recommended. ^[15] Objective response rates with rapalogs in clinical trials are modest and variable, and identifying biomarkers predicting response and drug combinations with improved efficacy remains critical. ^[1]