Eph / Ephrin projects
We discovered EphA3 in the cancer cells of a patient suffering from childhood leukaemia. This gene is not normally active in blood cells but is highly expressed in a number of leukaemias and lymphomas. We have now shown that a proportion of other cancers also express EphA3 but it is not expressed in any normal tissues at significant levels. We are investigating this gene and a number of other members of the large Eph gene family.
EphA3 in cancer therapy
We are investigating a monoclonal antibody directed at EphA3 as a potential anti-cancer therapy. In a pre-clinical leukaemia model this has proved very effective at inhibiting leukaemia cell growth, we are now working with a US company on a form of the antibody which could be used in humans.
EphA1 and 2 in tissue function and cancer
Two other members of the family found in blood cells are also being investigated. Both are also found to be abnormally expressed in some cancers. We have developed antibodies to each of these to explore the distribution in leukaemia and other cancers.
We have made an extensive study of EphA4 which is expressed in blood cells, particularly the cells which give rise to platelets, and shown that it is also very important in normal spinal cord development. As a spin-off of our studies we are working with other scientists at University of Queensland on potential treatments for spinal injuries. We are continuing to look at EphA4 expression in leukaemia and in normal blood cells.
Bcl-2 family proteins in tumours
Most normal cells are programmed to die at a certain age or stage of development through a biochemical process called apoptosis. Up to that point the cells are protected by anti-apoptosis proteins including Bcl-2 and related proteins, one of which is Mcl-1. Some cancers over-express one or more of these proteins as a way of preventing apoptosis, thus allowing the tumour to survive and grow inappropriately. In leukaemia, including chronic lymphocytic leukaemia (CLL), high levels of Mcl-1 appear to correlate with a more aggressive course.
Inhibiting Mcl1 in tumours
We are studying the effect of inhibiting Mcl-1 on tumour survival. These studies show that ‘knocking down’ Mcl-1 can sensitise tumour cells to chemotherapy and other agents which trigger the apoptosis mechanism.
Mcl1 promoter analysis
These studies have shown that the mechanism of switching on the Mcl-1 gene is more complex than previously recognised. Indeed, these studies show that the proposed mechanism thought to explain over-expression in CLL is incorrect. We have identified a transcription factor binding site in the gene which has a major effect on Mcl-1 expression.
Fat protocadherin in T ALL/lymphoblastic lymphoma
These forms of acute leukaemia are still devastating in most sufferers and there is an urgent need for new therapeutic approaches. We have shown that most cases express an abnormal form of the Fat protocadherin protein. We have shown that this abnormal form has a unique structure and we are investigating whether this is a therapeutic target.
The unit also contributes to a number of pre-clinical studies and early phase clinical trials of agents developed by other groups (academic and commercial). These studies are important in developing new therapies in Australia. They are critical in bringing in the expertise to translate our own research along the clinical development pathway.