Initial testing (stage 1) of the notch inhibitor PF-03084014, by the pediatric preclinical testing program

Pediatr Blood Cancer. 2014 Aug;61(8):1493-6. doi: 10.1002/pbc.25026. Epub 2014 Mar 24.

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.

Keywords: developmental therapeutics; notch inhibitors; preclinical testing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Child
  • Child, Preschool
  • Humans
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mice, SCID
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / metabolism
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / metabolism
  • Receptors, Notch / antagonists & inhibitors*
  • Tetrahydronaphthalenes / pharmacology*
  • Valine / analogs & derivatives*
  • Valine / pharmacology
  • Xenograft Model Antitumor Assays*

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • Receptors, Notch
  • Tetrahydronaphthalenes
  • Valine
  • nirogacestat