Poster Presentation 30th Lorne Cancer Conference 2018

New Treatments for High-Risk Acute Lymphoblastic Leukaemia in Children (#178)

Conner Jones 1 , Richard Lock 1
  1. Leukaemia Biology, Children’s Cancer Institute, Sydney, NSW, Australia

Acute lymphoblastic leukaemia (ALL) is the malignant growth of lymphoblasts – precursor cells to lymphocytes. Despite its now 90% survival rate, there still remain subtypes of the disease with poor survivability. Ph-like ALL is one of these high-risk subtypes, characterised by its unregulated tyrosine kinase activity. A molecular target for the treatment of Ph-like ALL is the Janus Kinase (JAK) protein, inhibited by the JAK1/2 inhibitor ruxolitinib. Like most chemotherapeutic drugs, ruxolitinib has low potency as a single agent and shows more efficacy in treating Ph-like ALL when combined with other drugs. In conjunction with colleagues at the Children’s Cancer Institute, drug combination of ruxolitinib and the glucocorticoid dexamethasone has been identified as a potential effective combination in the treatment of Ph-like ALL. Cytotoxicity assays in fixed-ratio combination of ruxolitinib and dexamethasone confirmed and quantified potent synergistic effects in cell lines of Ph-like ALL. Mechanistic analysis, via immunoblotting and DNA-binding assays, was performed to elucidate the mechanism of synergy between the two drugs. No impact of ruxolitinib on the dexamethasone mechanism of action, like the nuclear translocation or DNA-binding of the glucocorticoid receptor, could be detected. Intriguingly, dexamethasone appears to have some inhibitory impact on tyrosine kinase mechanisms by reducing STAT5 phosphorylation, although the mechanism of this action is likely indirect and remains unclear. Combination of this tyrosine kinase inhibition alongside the same effects of ruxolitinib may maximise the inhibition, explaining the synergy. Further mechanistic analysis is required to grasp complete understanding of the mechanism of synergy of the two drugs.