Defining mechanisms of response to combined Cyclin-dependent kinase 9 (CDK9) and BCL-2 inhibition in high-risk B-cell acute lymphoblastic leukaemia

This project is suitable for Honours, Masters (by Research) and PhD students. Background Despite major advances in targeted therapies and immunotherapy, relapse remains a leading cause of treatment failure in children and adults with high-risk B-cell acute lymphoblastic leukaemia (B-ALL). Venetoclax has demonstrated promising activity in selected B-ALL subtypes; however, therapeutic resistance frequently limits the durability of response. Our laboratory previously demonstrated that simultaneous inhibition of BCL-2 and MCL-1 using venetoclax and the Cyclin-dependent kinase 9 (CDK9) inhibitor alvocidib produces potent synergistic anti-leukaemic activity across multiple high-risk B-ALL models, including patient-derived xenografts. CDK9 regulates transcription of key pro-survival proteins, including MCL-1, thereby lowering the apoptotic threshold and sensitising leukaemia cells to BCL-2 inhibition. Building on this work, the next challenge is to understand why some leukaemias respond exceptionally well to combined CDK9 and BCL-2 inhibition while others develop resistance, and to identify biomarkers that can guide patient selection for future clinical translation. Aim This project will investigate the molecular and metabolic mechanisms governing response and resistance to combined Cyclin-dependent kinase 9 (CDK9) and BCL-2 inhibition using clinically annotated patient-derived B-ALL models. Students will receive training in cutting-edge translational cancer research techniques, including: establishment and treatment of clinically annotated patient-derived xenograft (PDX) models of high-risk B-ALL evaluation of novel Cyclin-dependent kinase 9 (CDK9) inhibitor-based combination therapies with venetoclax single-cell RNA sequencing to characterise transcriptional responses and identify therapy-resistant cellular populations comprehensive genomic profiling using the ALLHaem next-generation sequencing panel quantitative proteomic profiling to identify signalling pathways associated with treatment response and resistance BH3 profiling and apoptosis assays to define mitochondrial apoptotic priming flow cytometry, molecular biology and functional drug screening CRISPR-Cas9 gene editing to functionally validate candidate resistance mechanisms integration of genomic, transcriptomic, proteomic and functional datasets to identify clinically actionable biomarkers and mechanisms of therapeutic resistance. Depending on the level of the project (Honours or PhD), students may also investigate mechanisms of acquired resistance using longitudinal patient-derived models and evaluate novel biomarker-driven combination therapies designed to overcome therapeutic resistance. This project provides a unique opportunity to work within a highly translational research program with direct access to clinically annotated patient samples, patient-derived xenograft models, clinician scientists and national and international collaborators. Findings from this work will directly inform the development of biomarker-driven clinical trials for patients with high-risk B-cell acute lymphoblastic leukaemia.