Preclinical evaluation of MCL-1-targeting PROTACs in high-risk acute leukaemia

This project is suitable for Honours, Masters (by Research) and PhD students. Background Acute myeloid leukaemia (AML) and B-cell acute lymphoblastic leukaemia (B-ALL) remain difficult to cure, particularly in patients with relapsed or treatment-resistant disease. Many leukaemias depend on anti-apoptotic BCL-2 family proteins, including MCL-1 and BCL-2, to evade cell death. Although BCL-2 inhibition with venetoclax has transformed treatment for selected patients, resistance frequently emerges through adaptive survival mechanisms, including increased dependence on MCL-1. Proteolysis-targeting chimeras (PROTACs) are an emerging therapeutic class that eliminate disease-driving proteins by recruiting them to the ubiquitin-proteasome system for degradation. Unlike conventional inhibitors, PROTACs remove the target protein from the cell, potentially producing deeper and more durable anti-tumour responses. This project will evaluate a novel MCL-1-targeting PROTAC in clinically relevant models of AML and B-ALL, with a particular focus on defining mechanisms of therapeutic response, resistance and synergy with venetoclax. Aim This project will investigate the preclinical activity of a novel MCL-1-targeting PROTAC in high-risk AML and B-ALL using clinically relevant patient-derived models. Students will receive training in cutting-edge translational research techniques, including: patient-derived xenograft (PDX) models targeted therapy combination studies molecular mechanisms of therapeutic response and resistance single-cell transcriptomics, proteomics and genomic profiling apoptosis assays, flow cytometry and molecular biology biomarker discovery and translational data integration. This project provides an exciting opportunity to contribute to the development of next-generation targeted therapies for patients with high-risk acute leukaemia. Essential criteria Minimum entry requirements can be found here: https://www.monash.edu/admissions/entry-requirements/minimum