title: Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models.
abstract: Ridaforolimus is a nonprodrug rapamycin analogue that potently inhibits mTOR and has shown significant activity in patients with metastatic sarcoma and endometrial cancer, two diseases where high unmet need remains. Here, we evaluated the activity of ridaforolimus in preclinical models of these tumor types and used these models to explore molecular correlates of sensitivity. The in vitro sensitivity of a panel of sarcoma and endometrial cancer cell lines was established by measuring the effect of ridaforolimus on cell proliferation rate, revealing broad inhibition at low nanomolar concentrations. Additional benefit was found when ridaforolimus was combined with agents used to treat sarcoma and endometrial cancer patients. In vivo, potent antitumor activity of ridaforolimus associated with inhibition of mTOR signaling was observed in sarcoma and endometrial xenograft models. Immunoblot analysis was conducted to assess the expression and activation state of multiple signaling proteins in the phosphoinositide-3-kinase/AKT/mTOR and cell-cycle pathways. In endometrial but not sarcoma cell lines, the absence of PTEN or elevated levels of phosphorylated or total AKT was associated with greater sensitivity. However, in both tumor types, the proportion of cells in the G(0)-G(1) phase before treatment correlated significantly with ridaforolimus sensitivity. Consistent with this, expression of several G(1) phase cell-cycle proteins, notably p21 and p27, was higher in more sensitive lines. These results underscore the promise of ridaforolimus as a single agent or combination treatment of these tumor types and suggest novel potential predictive biomarkers of sensitivity to an mTOR inhibitor based on cell-cycle status.
authors.affiliation: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139, USA. Rachel.squillace@ariad.com
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Squillace
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.forename: Michelle
authors.initials: M
authors.lastname: Cookson
authors.forename: Scott D
authors.initials: SD
authors.lastname: Wardwell
authors.forename: Lauren
authors.initials: L
authors.lastname: Moran
authors.forename: David
authors.initials: D
authors.lastname: Clapham
authors.forename: Frank
authors.initials: F
authors.lastname: Wang
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C515074:ridaforolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus