Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design

Mol Cancer Ther. 2010 Jun;9(6):1618-28. doi: 10.1158/1535-7163.MCT-10-0034. Epub 2010 Jun 8.

Abstract

Aberrant regulation of Notch signaling has been implicated in tumorigenesis. Proteolytic release of the Notch intracellular domain (NICD) by gamma-secretase plays a key role in Notch-dependent nuclear signaling. gamma-Secretase is an attractive pharmaceutical target for therapeutic intervention in cancer. We describe the potent antitumor effects of PF-03084014, a small molecule that is a reversible, noncompetitive, and selective gamma-secretase inhibitor. The ability of PF-03084014 to inhibit gamma-secretase activity was shown by the reduction of endogenous NICD levels and by the downregulation of Notch target genes Hes-1 and cMyc in the T-cell acute lymphoblastic leukemia (T-ALL) cell line HPB-ALL. PF-03084014 caused cell growth inhibition of several T-ALL cell lines via cell cycle arrest and induction of apoptosis. PF-03084014 treatment also resulted in robust NICD reduction in HBP-ALL xenograft models. Broad antitumor efficacy at well-tolerated dose levels was observed in six Notch-dependent models. Additional mechanism-of-action studies showed inhibition of tumor cell proliferation and induction of apoptosis in HPB-ALL tumors, suggesting that the antitumor activity of PF-03084014 may be mediated by its direct effects on tumor cell growth or survival. Further studies on PF-03084014-induced gastrointestinal toxicity identified an intermittent dosing schedule that displayed reduced body weight loss and sustained antitumor efficacy. We also showed that glucocorticoids abrogated PF-03084014-induced gastrointestinal toxicity and delayed administration of glucocorticoids did not compromise its protection effect. Collectively, the results show that inhibition of Notch signaling by PF-03084014 while minimizing gastrointestinal toxicity presents a promising approach for development of therapies for Notch receptor-dependent cancers. This compound is being investigated for the treatment of T-ALL and advanced solid tumors in phase I clinical trials.

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Clinical Trials as Topic* / standards
  • Dexamethasone / administration & dosage
  • Dexamethasone / pharmacology
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Gastrointestinal Tract / drug effects*
  • Gastrointestinal Tract / pathology
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Protease Inhibitors / administration & dosage
  • Protease Inhibitors / pharmacology*
  • Protease Inhibitors / toxicity
  • Protein Structure, Tertiary
  • Receptors, Notch / chemistry
  • Receptors, Notch / metabolism
  • Tetrahydronaphthalenes / administration & dosage
  • Tetrahydronaphthalenes / adverse effects*
  • Tetrahydronaphthalenes / pharmacology*
  • Time Factors
  • Treatment Outcome
  • Valine / administration & dosage
  • Valine / adverse effects
  • Valine / analogs & derivatives*
  • Valine / pharmacology
  • Xenograft Model Antitumor Assays*

Substances

  • Antineoplastic Agents
  • Protease Inhibitors
  • Receptors, Notch
  • Tetrahydronaphthalenes
  • Dexamethasone
  • Amyloid Precursor Protein Secretases
  • Valine
  • nirogacestat