title: High-throughput screening of human leukemia xenografts to identify dexamethasone sensitizers.
abstract: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Glucocorticoids (e.g., dexamethasone) form a critical component of chemotherapy regimens for pediatric ALL, and the initial response to glucocorticoid therapy is a major prognostic factor, where resistance is predictive of poor outcome. We have previously established a clinically relevant ALL xenograft model, consisting of primary pediatric ALL biopsies engrafted into immune-deficient mice, in which in vitro and in vivo dexamethasone sensitivity significantly correlated with patient outcome. In this study, we used high-throughput screening (HTS) to identify novel compounds that reverse dexamethasone resistance in a xenograft (ALL-19) derived from a chemoresistant pediatric ALL patient that is representative of the most common pediatric ALL subtype (B-cell precursor [BCP-ALL]). The compound 2-(4-chlorophenoxy)-2-methyl-N-(2-(piperidin-1-yl)phenyl)propanamide showed little cytotoxic activity alone (IC50 = 31 µM), but when combined with dexamethasone, it caused a marked decrease in cell viability. Fixed-ratio combination assays were performed against a broad panel of dexamethasone-resistant and -sensitive xenografts representative of BCP-ALL, T-cell ALL, and Mixed Lineage Leukemia-rearranged ALL, and synergy was observed in six of seven xenografts. We describe here the development of a novel 384-well cell-based high-throughput screening assay for identifying potential dexamethasone sensitizers using a clinically relevant ALL xenograft model.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia School of Women's and Children's Health, University of New South Wales, Sydney, Australia.
authors.forename: Cara E
authors.initials: CE
authors.lastname: Toscan
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Failes
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia ACRF Drug Discovery Centre for Childhood Cancer, Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Arndt
authors.affiliation: Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia School of Women's and Children's Health, University of New South Wales, Sydney, Australia rlock@ccia.unsw.edu.au.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D015203:Reproducibility of Results; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D003907:Dexamethasone
keywords: cell-based screening; dexamethasone sensitizer; drug resistance; pediatric leukemia; xenograft