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

Hernan Carol1, John M Maris, Min H Kang

  • 1Children's Cancer Institute Australia for Medical Research, Randwick, NSW, Australia.

Pediatric Blood & Cancer
|March 26, 2014
PubMed

Insights

PF-03084014, a gamma-secretase inhibitor, showed limited effectiveness in preclinical pediatric cancer models. The drug did not achieve significant inhibition in vitro or objective responses in vivo, indicating minimal single-agent activity.

Area of Science:

  • Pharmacology
  • Oncology
  • Cancer Research

Background:

  • Gamma-secretase inhibitors are investigated for cancer therapy.
  • Notch signaling pathway plays a role in various cancers.

Purpose of the Study:

  • To evaluate the preclinical activity of PF-03084014, a gamma-secretase inhibitor.
  • To assess the efficacy of PF-03084014 in pediatric preclinical models.

Main Methods:

  • In vitro testing against a panel of cell lines (1.0 nM to 10 microM).
  • In vivo testing using solid tumor and ALL xenograft models.
  • Oral administration of PF-03084014 twice daily on specific treatment cycles.

Main Results:

  • Limited in vitro activity observed, with no cell line showing ≥50% inhibition.
  • Significant differences in event-free survival (EFS) distribution in 40% of solid tumor xenografts.
  • One acute lymphoblastic leukemia (ALL) xenograft (lacking NOTCH1 mutation) showed EFS differences.
  • No objective responses were observed in any xenograft models.

Conclusions:

  • PF-03084014 demonstrated limited single-agent activity in vitro and in vivo.
  • The gamma-secretase inhibitor showed minimal efficacy in the studied pediatric preclinical models.
Keywords:
developmental therapeuticsnotch inhibitorspreclinical testing

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