From the International Innovation Journal. Download the original article here.
Professor Andrew Boyd, Head of the Leukaemia Foundation Research Unit at QIMR, has been studying EphA3 – a gene not normally active in blood cells, but highly expressed in a number of leukaemias and lymphomas.
The journey from the initial identification of the antibody to the stage of clinical testing has been long. As a haematologist, a strong motivation for pursuing a research career was the thought that I might do something which improved the lot of all patients with leukaemia and related diseases. In some measure I have contributed to other projects which have had this ultimate result, but the KB004 project has a special place as it originated in my own lab. Thus, although it now involves two other research groups in Australia and a US company, there is a sense of nearing the goal I set out to achieve when I first started my research career.
What provided the inspiration for the focus of your research?
In a broad sense the desire to find something new has always been a significant factor. Also, I still treat cancer patients and thus there is a desire to discover something which will make a
Currently, you are exploring the biology of leukaemia and other cancers through studies of cancer-associated proteins.What are the main aims and objectives of this work?
We want to find genes or proteins that are involved in some way in the cancer process and to identify potential targets for therapy. We hope that this will increase wider understanding of cancer.
How would you explain the functions of EphA3, and its link to cancer in particular?
EphA3 is a member of the tyrosine kinase family, a large group of genes which are particular to animals, and control cell growth and movement. Many members of this family are perturbed in distinct cancers. The Eph genes act in varying ways in different cancer types, but EphA3 expression is increased in groups of glioma, leukaemia, melanoma and other cancer types. In some cases the role of EphA3 is uncertain. However, in glioma our collaborative research group (in particular Dr Bryan Day) has shown that EphA3 is critical for the propagation of tumour forming cells. Thus targeting EphA3 can extinguish the tumour in preclinical models and has defi nite therapeutic potential.
How did you go about growing billions of leukaemic cells to extract the protein for amino acid sequence determination?
This is dependent on establishing cell lines from the original cancer. It isn’t always straightforward, but in the case of EphA3 we had a cell line derived from the blood of a leukaemia patient which initially grew slowly in cell culture. We identified a mutant of these cells which grew rapidly and expressed more EphA3 protein. This was critical in expanding the cells to very large numbers.
What was the reason for using a leukaemic cell from a child in your research?
We were interested in genes that might be implicated in pre B acute lymphoblastic leukaemia (ALL). The line we used was only recently derived – hence we reasoned that abnormalities might be present in the original leukaemia, rather than being something which arose in the laboratory.
We have applied this principle to our more recent work on glioma where EphA3 seems to have an even more central role in tumour growth.
What research are you conducting into other members of the EphA3 family found in blood cells?
A number of Eph family members may have a role in leukaemia and lymphoma and we are studying three more members of this family (A2, A7 and B4) to determine if they have a role in blood and other cancers.
EphA2 appears to have a similar role to EphA3 in glioma.
Could you tell us about your current work in the KB004 project with US company KaloBios Pharmaceuticals, Inc? How will the phase I clinical trial lead on to further testing?
The phase I trial of the antibody is in progress and if successful will lead on to trials in combination with current therapies on a larger scale. In case the antibody alone is insufficient, we are also working on coupling the antibody to a drug or a radioactive isotope to enhance its activity.
Finally, what challenges have you faced in the long journey to clinical trials of KB004, working with industry and collaborators, and how have you overcome them?
Initially the potential to treat was not clear and hence it was difficult to find a partner. Fortunately, KaloBios was interested and the work has proceeded well since then.