Improved treatments for high-risk paediatric acute lymphoblastic leukaemia

Abstract

Acute lymphoblastic leukaemia (ALL) is a highly heterogeneous disease which can be divided into various subtypes based on cytogenetics and recurrent chromosomal alterations. By associating clinical outcomes, recurrent mutations can be used as markers in risk stratification. Among other factors, risk-directed treatments based on specific genomic alterations have contributed significantly to the high overall cure rate of ALL. However, patients classified as high-risk are still in need of better treatment strategies. One such subtype of high-risk ALL is termed the Philadelphia-like (Ph-like) ALL. Results from two clinical trials conducted by the Children’s Oncology Group have uniformly reported the relatively poor outcome of Ph-like patients compared to non-Ph-like. Hence, the main aim of this study was to identify novel effective treatments for paediatric Ph-like ALL. The main strategy used in this study was by targeting the cytokine receptor-like factor 2 (CRLF2) signalling axis. CRLF2 signalling is important in Ph-like ALL as up to 50% patients overexpress this receptor tyrosine kinase as a result of recurrent genomic alterations. In children, CRLF2 overexpression is correlated to poor outcome in the high-risk patients, but not the standard-risk, further suggesting the potential therapeutic value of CRLF2 in high-risk ALL.

While clinically approved agents targeting CRLF2 do not exist, small molecule inhibitors can be used to target signalling kinases downstream of CRLF2. Through a phosphoproteomic approach, downstream tyrosine kinases activated by CRLF2 and its ligand were identified in this study. Subsequently, a rationally designed combination treatment of the tyrosine kinase inhibitors BMS-754807 and ponatinib was tested against patient-derived xenograft (PDX) models of Ph-like ALL and showed remarkable in vitro efficacy. The combination was further validated in preclinical models of Ph-like ALL using immunodeficient mice, albeit with disappointing in vivo efficacy results. In addition, investigations were carried out to determine the mechanism of sensitivity of Ph-like ALL cells to the SMAC mimetic birinapant, by studying epigenetic regulation of tumour necrosis factor receptor 1 (TNFR1) expression. Collectively, multifaceted approaches were utilised in this study for the overall aim of improving the clinical outcomes of children with Ph-like ALL.