Poster Presentation 37th Lorne Cancer Conference 2025

Efficacy of novel targeted therapies in Down syndrome acute lymphoblastic leukaemia (#225)

Kunjal Panchal 1 2 , Carlos A Bonilla 1 , Vivien Nguyen 1 , Jesse Armitage 1 , Maryam Simad 1 , Grace Chua 3 , Shannon Carey-Smith 1 2 , Hannah Smolders 3 , Richard Francis 1 , Laurence Cheung 2 3 , Rishi S Kotecha 3 4 , Sebastien Malinge 1
  1. Translational Genomics in Leukaemia, The Kids Research Institute Australia, Nedlands, WA, Australia
  2. Curtin University, Bentley, WA, Australia
  3. Leukaemia Translational Research, The Kids Research Institute Australia, Nedlands, WA, Australia
  4. Perth Childrens Hospital, Nedlands, WA, Australia

Outcomes for paediatric leukaemia have significantly improved in recent decades, however it still accounts for more than 20% of cancer-related deaths in children, largely due to relapse. The survival for children experiencing relapse remains below 50%, and survivors face life-long side effects caused by treatment intensification. These poor outcomes are exemplified in children with Down Syndrome (DS) who develop acute lymphoblastic leukaemia (named DS-ALL), a community who have higher rates of treatment-related mortality and relapse. Better and safer treatments are urgently needed for these vulnerable children as they also have many other health issues. Until recently, no clinically relevant DS-ALL models of were available to study nor design tailored therapies.

Here, we generated a unique cohort of DS-ALL patient-derived xenografts (PDXs), from patient specimens collected Australia-wide, and comprehensively characterized them at the transcriptomic, phenotypic, and functional levels to facilitate the discovery of new actionable targets. We also established the world-first DS-ALL cell lines representative of the most common DS-ALL genetic subtypes. We used the DS-ALL cell lines to screen more than 6000 compounds that target key cellular functions (including epigenetic, cell cycle, apoptosis). From this drug scree, among the most potent drug class, we found Histone Deacetylases (HDAC) and Cyclin-dependent kinases (CDK) inhibitors; these are currently being validated in vitro in dose-response assays, alone and in combination with standard-of-care agents seeking a synergistic effect. Ultimately, the efficacy of the best drug combination using HDAC/CDK inhibitors will be tested in vivo in several DS-ALL PDXs to select the most potent agents in a true preclinical setting.

Our long-term goal is to facilitate the translation of new inhibitors with high efficacy and low toxicity into the clinic, to ultimately improve the quality of care, the quality of life and long-term outcomes for children with DS who develop DS-ALL, and beyond DS.