mTOR pathway and mTOR inhibitors as agents for cancer therapy.
Research into mTOR, mammalian Target Of Rapamycin as an important drug target continues to be extremely interesting, both in terms of the increased molecular knowledge being acquired at the basis of various human diseases, and also for possible applications in drug cancer therapy. The mTOR signaling system plays a key role in several transduction pathways that are necessary for cell cycle progression and cellular proliferation. Drugs known as mTOR inhibitors have been included in ongoing and in recently completed cancer trials. New insights into the mTOR signaling system are helping to clarify the functionality of key mTOR components, and especially their possible role in apoptosis, angiogenesis and tumor progression. Three other molecules, already approved for therapeutic use and being commercialized (Everolimius, Temsirolimus and Zotarolimus) are added to Rapamycin (also known as Sirolimus), the parent drug of the mTOR inhibitors. Of these, only Temsirolimus is currently approved in the treatment of renal cell carcinoma, while the others are approved for organ transplant rejection and coronary artery restenosis. There are at least 10 other molecules currently under development for clinical and preclinical studies. This review offers an updated synopsis of the mTOR signaling system, in particular as regards relevant aspects of cancer research, looks at the known mTOR inhibitors and gives a systematic vision of current trials for each individual molecule subject to clinical investigation.
Baldo
Paolo
P
Drug Information Centre, National Cancer Institute CRO-IRCCS, Aviano, Italy.
Cecco
Sara
S
Giacomin
Elisa
E
Lazzarini
Renzo
R
Ros
Barbara
B
Marastoni
Stefano
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases