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 M. Paietta, Janis Racevskis, Peter H. Wiernik, Jacob M. Rowe, John Jakubczak, Sophia Randolph, Carlos Cordon-Cardo, Adolfo A. Ferrando

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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 2012

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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Amyloid Precursor Protein Secretases
Glucocorticoids
Therapeutics
Goblet Cells
2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide
Glucocorticoid Receptors
Metaplasia
Tumor Burden
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Heterografts
Dexamethasone
Up-Regulation
T-Lymphocytes
Cell Line
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. / Samon, Jeremy B.; Castillo-Martin, Mireia; Hadler, Michael; Ambesi-Impiobato, Alberto; Paietta, Elisabeth M.; Racevskis, Janis; Wiernik, Peter H.; Rowe, Jacob M.; Jakubczak, John; Randolph, Sophia; Cordon-Cardo, Carlos; Ferrando, Adolfo A.

In: Molecular Cancer Therapeutics, Vol. 11, No. 7, 07.2012, p. 1565-1575.

Research output: Contribution to journalArticle

Samon, JB, Castillo-Martin, M, Hadler, M, Ambesi-Impiobato, A, Paietta, EM, Racevskis, J, Wiernik, PH, Rowe, JM, Jakubczak, J, Randolph, S, Cordon-Cardo, C & Ferrando, AA 2012, 'Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia', Molecular Cancer Therapeutics, vol. 11, no. 7, pp. 1565-1575. https://doi.org/10.1158/1535-7163.MCT-11-0938
Samon, Jeremy B. ; Castillo-Martin, Mireia ; Hadler, Michael ; Ambesi-Impiobato, Alberto ; Paietta, Elisabeth M. ; Racevskis, Janis ; Wiernik, Peter H. ; Rowe, Jacob M. ; Jakubczak, John ; Randolph, Sophia ; Cordon-Cardo, Carlos ; Ferrando, Adolfo A. / Preclinical analysis of the γ-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 7. pp. 1565-1575.
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