We asked Professor Alex Bullock for an update on the team’s work:
As you may know, most of the money raised by our supporters goes towards funding FOP research, including maintaining the work of our Oxford University Research Team. We last interviewed Professor Alex Bullock in May 2014 just before our first FOP Friends Conference and Family Gathering, and since then there has been a lot to catch up on…
Who currently makes up the research team at Oxford University?
The research team now combines staff working on the ACVR1 gene in the context of two distinct paediatric diseases, FOP and the rare brain tumour DIPG. The core FOP group comprises Dr Eleanor Williams, who is funded through your donations, as well as Miss Elizabeth Brown, who is a second year PhD student funded by an Oxford-The Simcox Family Graduate Scholarship. The Brain Tumour Charity provides additional support for Dr Jong Fu Wong and in future a further research assistant that we hope to recruit soon. Finally, Dr Roslin Adamson has been supported for the past year by charitable funds coming via M4K Pharma for DIPG research. She will be leaving us in March and will be replaced by a 6 month intern Miss Elisabeth Rothweiler. The team are supervised by myself with additional help from my departmental colleague Dr Gillian Farnie. Emeritus Professor Jim Triffitt also continues to provide his oversight from retirement.
Miss Elizabeth Brown, Dr Roslin Adamson and Dr Jong Fu Wong at the 2018 FOP Conference and Family Gathering in Manchester, UK
Over the last five years what advancements have been made by the Oxford Team?
Our most significant finding has been the clinical drug candidate saracatinib (also known as AZD0530), which we identified as a highly effective inhibitor of the FOP causative protein ACVR1 (also known as ALK2). As we’ve reported previously, saracatinib was first developed by AstraZeneca for the treatment of ovarian cancer. While it did not show sufficient benefit for drug approval in this condition it has been made available by AstraZeneca for testing in other diseases. Importantly, saracatinib has now been tested in over 700 people and was shown to be well tolerated when taken as a daily tablet. We are currently completing the necessary legal paperwork to start a new trial using saracatinib in FOP later this year. As soon as we have more information we will communicate this through FOP Friends. In addition, we have been studying the root cause of FOP at the molecular level. All cases result from tiny changes in the ACVR1 gene (typically one erroneous letter – A, C, G or T in DNA – out of 1530 letters in the coding sequence). As a result, a faulty protein is made with one erroneous amino acid out of 509. We’ve been able to solve the 3D structure of one of these faulty proteins and have produced several others for functional analyses. It has been hypothesized that the faulty protein may simply have broken its shackles (e.g. tight binding to the FKBP12 protein) like a rocket detaching from a launch pad. Our experiments confirm this effect, but also suggest that the FOP rocket has an extra engine. Fortunately, drugs such as saracatinib can bind to the FOP protein to switch the rocket off again.
What are your short and long-term plans for future research?
With a current IFOPA project grant we are conducting a feasibility study to test whether other more unique drug binding pockets can be utilised on the FOP protein. Targeting such sites with small molecule inhibitors would allow the longer term development of a next generation drug with the hope of it having the fewest side effects. We are also exploring potential synergies between drug development for FOP and the brain cancer DIPG. Both groups of scientists are interested in the same faulty ACVR1 protein, but drugs for DIPG are desired that cross the blood-brain barrier efficiently to kill tumour cells. Dual action drugs that could potentially work in both diseases may include so called “epigenetic inhibitors”. These can control non-heritable factors such as whether DNA is packaged up for storage, or left open for the cell’s machinery to convert this information into functional proteins and action. In the short to medium term, we would also like to understand more about the molecular mechanisms of FOP. What factors contribute to the FOP rocket? In the long term, we hope that FOP will have a safe and effective treatment and that individuals with FOP will no longer rely on researchers to establish a cure.
Is there anything else you would like to add?
In addition to her FOP research role, a proportion of Dr Eleanor Williams’ post is funded by Wellcome for public engagement activities. Thus, over the past year Ellie has attended several science fairs including the Headington Festival in June, Oxford Science Festival in October, and Oxford Open Doors, where she gave the public tours of the laboratory as part of an annual city wide event in September. This coming year she will be attending the ATOM festival in Abingdon on the 24th of March and will be involved in the Cowley Road Carnival on the 7th of July. She will also be attending a Diamond Light Source open day at Harwell, Oxfordshire (date TBC). In other exciting news, Ellie has been collaborating with the Science Museum in London to create part of a display on drug discovery where she has used the FOP protein as an example of how drug design can work. This should be part of a new permanent display and we are very grateful to FOP Friends and Nicky Williams for providing a wonderful quote for the museum to use to go with our images. As ever, we are always happy to be contacted by anyone in the FOP community who is interested in seeing the laboratory and learning what we do.
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