mTOR-targeted therapy of cancer with rapamycin derivatives.
Rapamycin and its derivatives (CCI-779, RAD001 and AP23576) are immunosuppressor macrolides that block mTOR (mammalian target of rapamycin) functions and yield antiproliferative activity in a variety of malignancies. Molecular characterization of upstream and downstream mTOR signaling pathways is thought to allow a better selection of rapamycin-sensitive tumours. For instance, a loss of PTEN functions results in Akt phosphorylation, cell growth and proliferation; circumstances that can be blocked using rapamycin derivatives. From recent studies, rapamycin derivatives appear to display a safe toxicity profile with skin rashes and mucositis being prominent and dose-limiting. Sporadic activity with no evidence of dose-effect relationship has been reported. Evidence suggests that rapamycin derivatives could induce G1-S cell cycle delay and eventually apoptosis depending on inner cellular characteristics of tumour cells. Surrogate molecular markers that could be used to monitor biological effects of rapamycin derivatives and narrow down biologically active doses in patients, such as the phosphorylation of P70S6K or expression of cyclin D1 and caspase 3, are currently evaluated. Since apoptosis induced by rapamycin is blocked by BCL-2, strategies aimed at detecting human tumours that express BCL-2 and other anti-apoptotic proteins might allow identification of rapamycin-resistant tumours. Finally, we discuss current and future placements of rapamycin derivatives and related translational research into novel therapeutic strategies against cancer.
Vignot
S
S
Department of Oncology, Hospital Saint Louis, Paris Department of Medical Oncology, Beaujon University Hospital, Clichy, France.
Faivre
S
S
Aguirre
D
D
Raymond
E
E
D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus