Phone:08 8128 4340
Bachelor of Science (Biomedical)
Honours Project: Investigating the efficacy of novel and combination therapies in Ph-like ALL
Relapsed Acute Lymphoblastic Leukaemia (ALL) is a significant medical problem in children and adults. Recent advances in genomic profiling techniques highlighted the genetic heterogeneity of the disease; subgroups of patients harbouring a diverse range of genetic fusions exist. Of importance are two new, high-risk ALL subtypes (Ph+ and Ph-like ALL) which respond poorly to current chemotherapeutic regimens but which are targetable with safe and highly potent drugs already in clinical use.
Ph-like ALL is characterized by different genetic alterations including fusion genes involving ABL1 and ABL2 kinases:
- PAG1-ABL2, RCSD1-ABL2, ABL2-ZC3HAV1
- RANBP2-ABL1, RCSD1-ABL1, SNX2-ABL1, ZMIZ1-ABL1, NUP214-ABL1, ETV6-ABL1
ABL fusions can typically be targeted with tyrosine kinase inhibitors such as dasatinib, imatinib and nilotinib, which are used to treat patients with chronic myeloid leukaemia (CML). There is also a new allosteric inhibitor called ABL001 that has demonstrated efficacy against the BCR-ABL1 fusion most commonly observed in CML patients.
This project will investigate the efficacy of ABL001 in in vitro models of leukaemia and comprises the following aims:
1) Create viral constructs containing fusion genes of interest for transduction of the Ba/F3 cell line
2) Generate cell lines stably expressing fusion genes of interest for in vitro investigations including efficacy of novel and combination drug treatments
Techniques used will include:
- PCR and bacterial cloning of Ph-like fusions
- Viral transfection and transduction of cell lines
- Western blotting
- Flow cytometry including phospho-flow and Annexin V/7AAD cell death assays
Before improved treatment of patients is effected, it is first critical to investigate the efficacy of an expanding repertoire of available therapies in the laboratory. Results from this project will be used to guide in vivo mouse models and will ultimately contribute to advancing the knowledge of drug efficacy and personalized medicine approaches in the treatment of patients with Ph-like ALL.