Mechanisms of glucocorticoid resistance in acute lymphoblastic leukaemia
Suitable for PhD or Honours students
A/Prof Richard Lock
Email: rlock@ccia.unsw.edu.au
Despite dramatic improvements in therapy, acute lymphoblastic leukaemia (ALL) remains one of the most common causes of death from disease in children, and a significant number of patients relapse and succumb to their disease. Glucocorticoids are an essential component of drug treatment regimens in paediatric ALL, and mechanisms of resistance are poorly understood. Several Honours/PhD projects are available on the central theme of glucocorticoid resistance, all of which will utilise a variety of cell and molecular biology techniques and a clinically relevant xenograft model of paediatric ALL. The projects are as follows:
1. Investigate mechanisms of epigenetic silencing of candidate pro-apoptotic genes in glucocorticoid-resistant ALL and develop strategies to reactivate silenced genes;
2. Optimise high throughput screens to identify and characterise small-molecules that reverse glucocorticoid resistance;
3. Carry out genome-wide analyses for the identification of glucocorticoid receptor target genes using ChIP-chip and/or ChIP-SEQ techniques.
New treatments for high risk acute leukaemia in children
Suitable for PhD or Honours students
A/Prof Richard Lock
Email: rlock@ccia.unsw.edu.au
Despite dramatic improvements in the survival of children with acute lymphoblastic leukaemia (ALL) over the past 40 years, relapsed ALL remains one of the most common causes of death from disease in children. A more rare form of acute leukaemia in children, acute myelogenous leukaemia (AML) is even less curable than ALL. Therefore, new treatments for relapsed or high-risk disease are urgently required. The Leukaemia Biology Program at CCIA is involved in national and international preclinical drug testing programs to prioritise new drugs for clinical trials in children with relapsed or refractory leukaemia. Several Honours/PhD projects are available within the Program to further study novel drugs that have shown significant activity against our paediatric ALL experimental models, and to identify new drugs with potential activity in ALL and AML. Potential projects investigating novel drugs could involve studying:
1. Molecular determinants of in vivo sensitivity or resistance;
2. Their molecular mechanism of action against leukaemia cells;
3. Whether they preferentially target leukaemia cells and not normal cells of the body; and
4. How best to combine them with established therapy.
Targeting leukaemic stem cells in paediatric leukaemia
Suitable for PhD or Honours students
A/Prof Richard Lock
Email: rlock@ccia.unsw.edu.au
Seminal research carried out in the adult acute myelogenous leukaemia (AML) field has shown that minor populations of leukaemia-initiating cells, or leukaemic stem cells (LSCs), are able to initiate and maintain the disease in laboratory models. Moreover, the relative resistance of LSCs to chemotherapeutic drugs may be responsible for post-treatment relapse in patients. A detailed understanding of the cell and molecular biological characteristics of LSCs would facilitate the identification of novel targets for the development of new drugs that more specifically target leukaemia cells, thereby reducing many of the toxic side-effects associated with chemotherapy treatment. In contrast with adult AML, LSCs in paediatric AML are relatively poorly characterised. This PhD project will aim to identify LSCs in paediatric AML, compare their cell and molecular biological characteristics with those of normal haematopoietic stems cells, and test novel therapies designed to specifically target leukaemic and not normal haematopoietic cells.
