title: Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program.
abstract: PF-03084014, a γ-secretase inhibitor, was tested against the PPTP in vitro cell line panel (1.0 nM to 10 μM) and against the in vivo xenograft panels (administered orally twice daily on Days 1-7 and 15-21). PF-03084014 demonstrated limited in vitro activity, with no cell line achieving ≥50% inhibition. PF-03084014 induced significant differences in EFS distribution in 14 of 35 (40%) solid tumor xenografts, and 1 of 9 ALL xenografts (which lacked a NOTCH1 mutation), but objective responses were not observed. PF-03084014 demonstrated limited single agent activity in vitro and in vivo against the pediatric preclinical models studied.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: E Anders
authors.initials: EA
authors.lastname: Kolb
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lyalin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D051880:Receptors, Notch; D013764:Tetrahydronaphthalenes; D014633:Valine; C550722:nirogacestat
keywords: developmental therapeutics; notch inhibitors; preclinical testing