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: Hernan Carol, John M Maris, Min H Kang, C Patrick Reynolds, E Anders Kolb, Richard Gorlick, Stephen T Keir, Jianrong Wu, Raushan T Kurmasheva, Peter J Houghton, Malcolm A Smith, Richard B Lock, Dmitry Lyalin
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 61 Issue 8 Pg. 1493-6 (Aug 2014) ISSN: 1545-5017 [Electronic] United States
• PMID: 24664981 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

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

Topics

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