title: Synergistic activity of the mTOR inhibitor ridaforolimus and the antiandrogen             bicalutamide in prostate cancer models.
abstract: Although androgen ablation therapy is the foundation of current prostate             cancer treatment, most patients ultimately develop castration-resistant disease.             One proposed mechanism to account for androgen receptor (AR) activity in the castrate             environment is via crosstalk with other signaling pathways. Specifically, reciprocal             interactions between the AKT/mTOR and AR pathways have been implicated in prostate             cancer progression. Here, we used the potent inhibitor ridaforolimus to target             mTOR signaling alone and in combination with AR blockade by bicalutamide to examine             the effect of abrogating these signaling pathways. Ridaforolimus treatment inhibited             the proliferation of all six prostate cancer cell lines examined with the greatest             sensitivity associated with loss of PTEN and elevated AKT/mTOR pathway activity.             Dual inhibition of the AR and mTOR signaling pathways provided further benefit             with the ridaforolimus-bicalutamide combination producing synergistic antiproliferative             effects in prostate cancer cells in vitro when compared with each agent alone.             Pharmacodynamic analysis confirmed that combination treatment resulted in full             inhibition of each of the respective pathways. Importantly, the ridaforolimus-bicalutamide             combination exhibited potent antitumor activity with parallel reductions in plasma             PSA levels in vivo. Taken together, ridaforolimus exhibited potent antiproliferative             and antitumor activity in prostate cancer models and the addition of bicalutamide             represents a potentially effective combination strategy for patient therapy.
authors.affiliation: Department of Biology, ARIAD Pharmaceuticals Inc., Cambridge, MA, 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: Scott D
authors.initials: SD
authors.lastname: Wardwell
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: D059002:Androgen Receptor Antagonists / Q000008:administration & dosage; D000813:Anilides / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000008:administration & dosage; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014105:Tosyl Compounds / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C515074:ridaforolimus; C053541:bicalutamide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017430:Prostate-Specific Antigen; D020123:Sirolimus