title: 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.affiliation: Department of Pathology, Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Samon
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martin
authors.forename: Michael
authors.initials: M
authors.lastname: Hadler
authors.forename: Alberto
authors.initials: A
authors.lastname: Ambesi-Impiobato
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: Janis
authors.initials: J
authors.lastname: Racevskis
authors.forename: Peter H
authors.initials: PH
authors.lastname: Wiernik
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.forename: John
authors.initials: J
authors.lastname: Jakubczak
authors.forename: Sophia
authors.initials: S
authors.lastname: Randolph
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003907:Dexamethasone / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014633:Valine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; D051881:Receptor, Notch1; D013764:Tetrahydronaphthalenes; D003907:Dexamethasone; D053829:Amyloid Precursor Protein Secretases; D014633:Valine; C550722:nirogacestat