Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia

Mol Cancer Ther. 2012 Jul;11(7):1565-75. doi: 10.1158/1535-7163.MCT-11-0938. Epub 2012 Apr 13.


T-cell acute lymphoblastic leukemias (T-ALL) and lymphomas are aggressive hematologic cancers frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of γ-secretase inhibitors (GSI). Here, we characterized the interaction between PF-03084014, a clinically relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Mechanistically PF-03084014 plus glucocorticoid treatment induced increased transcriptional upregulation of the glucocorticoid receptor and glucocorticoid target genes. Treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment effectively reversed PF-03084014-induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results warrant the analysis of PF-03084014 and glucocorticoids in combination for the treatment of glucocorticoid-resistant T-ALL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cluster Analysis
  • Dexamethasone / administration & dosage
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic / drug effects
  • Glucocorticoids / pharmacology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Receptor, Notch1 / antagonists & inhibitors
  • Receptor, Notch1 / metabolism
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / pharmacology*
  • Tetrahydronaphthalenes / toxicity
  • Valine / analogs & derivatives*
  • Valine / chemistry
  • Valine / pharmacology
  • Valine / toxicity


  • Antineoplastic Agents
  • Glucocorticoids
  • Receptor, Notch1
  • Tetrahydronaphthalenes
  • Dexamethasone
  • Amyloid Precursor Protein Secretases
  • Valine
  • nirogacestat