pf-3084014 and Precursor-T-Cell-Lymphoblastic-Leukemia-Lymphoma

Topics: Adolescent; Adult; Antineoplastic Agents; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Receptor, Notch1; Tetrahydronaphthalenes; Valine; Young Adult

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.

Topics: Amyloid Precursor Protein Secretases; Animals; Antineoplastic Agents; Cell Line, Tumor; Cluster Analysis; Dexamethasone; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Glucocorticoids; Humans; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Receptor, Notch1; Tetrahydronaphthalenes; Valine