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Abstract
Acute lymphoblastic leukaemia (ALL) is the most common cancer in children, and is a major cause of non-accidental death in childhood. Glucocorticoids, such as prednisolone and dexamethasone, are critical agents in the treatment of ALL. Early response to prednisolone monotherapy is highly prognostic of outcome, with poor responders having significantly inferior survival rates. However the mechanisms of glucocorticoid resistance are poorly understood, and identification of novel agents to reverse resistance could improve the outcomes for this high-risk group of patients.
The aim of this study was to investigate glucocorticoid resistance using an unbiased genome-wide approach. A panel of 10 ALL xenografts derived from children classified as prednisolone poor responders (PPRs) and matched prednisolone good responders (PGRs) was created using the NOD/SCID xenograft mouse model, and the in vitro and in vivo responses to dexamethasone determined. A pilot study was undertaken which established the optimal experimental design to investigate in vivo glucocorticoid-induced gene expression, and using this setup the in vivo dexamethasone-induced gene expression profiles of the xenograft panel was determined.
Two gene signatures of glucocorticoid resistance were generated from this data, and a third signature associated with in vivo glucocorticoid sensitivity of a separate xenograft cohort was derived using historical data. Interrogation of the Connectivity Map with each signature identified HSP90 inhibitors as agents which induced a complementary gene expression signature and thus could potentially reverse glucocorticoid resistance. Testing of the HSP90 inhibitor 17-DMAG demonstrated a moderate degree of synergy with dexamethasone in 3 PPR xenografts tested in vitro, but no synergy in vivo, potentially due to the toxicity of the vehicle to the mice. Glucocorticoid resistance in ALL can potentially be overcome with HSP90 inhibitors, and next generation inhibitors warrant further evaluation in an extended panel of glucocorticoid-resistant xenografts.