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

Jeremy B. Samon, Mireia Castillo-Martin, Michael Hadler, Alberto Ambesi-Impiobato, Elisabeth Paietta, Janis Racevskis, Peter H. Wiernik, Jacob M. Rowe, John Jakubczak, Sophia Randolph, Carlos Cordon-Cardo, Adolfo A. Ferrando

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1565-1575
Number of pages11
JournalMolecular cancer therapeutics
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Samon, J. B., Castillo-Martin, M., Hadler, M., Ambesi-Impiobato, A., Paietta, E., Racevskis, J., Wiernik, P. H., Rowe, J. M., Jakubczak, J., Randolph, S., Cordon-Cardo, C., & Ferrando, A. A. (2012). Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Molecular cancer therapeutics, 11(7), 1565-1575. https://doi.org/10.1158/1535-7163.MCT-11-0938