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

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.

• Authors: 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 7 Pg. 1565-75 (Jul 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22504949 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

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

Topics

• Amyloid Precursor Protein Secretases (antagonists & inhibitors, 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, metabolism)
• Receptor, Notch1 (antagonists & inhibitors, metabolism)
• Tetrahydronaphthalenes (chemistry, pharmacology, toxicity)
• Valine (analogs & derivatives, chemistry, pharmacology, toxicity)