Dr Adam Cribbs leads a computational biology group at the University of Oxford with a focus on systems biology, immunology, and epigenetics.

For Rare Disease Day, he provides insight into the 'weird and wonderful' world of science and shares how funding from the Bone Cancer Research Trust helps identify new potential targets for chordoma.

What was your BCRT-funded project about and how will it help patients?

This project was aimed at finding small molecules to help identify new therapeutic interventions for chordoma. The research was conducted in collaboration with Udo Oppermann at the University of Oxford, and Lucia Cottone and Adrienne Flanagan at University College London.

The initial phase involved screening a diverse array of compounds targeting various components of the chordoma cellular architecture, including epigenetic regulators, metabolic pathways, and kinase enzymes, among other potential targets.

There are many different types of protein found within cells, and we use very selective small molecule compounds to target them. We call these tool compounds, which bind and inhibit particular proteins. What we identified initially was around 30-40 hits which led to the chordoma cells dying.

The aim of the grant was to try and identify which targets we think could be beneficial to take forward to a drug development programme. If you want to take a drug to the clinic, you have to really understand the mechanism beforehand. We want to understand how these drugs work, and once we have understood this we want to see if they could progress towards the clinic to help treat patients.

We identified one compound which we ended up taking forwards. It is a Chinese herbal medicine that was adapted by a pharmaceutical company and is currently approved for treating scleroderma.

Given its established clinical use, our research team aimed to further investigate this compound's mechanism of action within chordoma using sophisticated laboratory models. The funding provided by the Bone Cancer Research Trust played a pivotal role in mitigating risks associated with this target, effectively reducing speculation and eliminating as many uncertainties as possible.

This medicine was found to reduce the tumour burden (total amount of cancer) in these models, indicating its potential as a new treatment for chordoma.

How did you come to specialise in this field?

I didn't expect to end up here! It happened by chance, it really was a combination of different factors coming together that sparked my interest in exploring whether drugs already on the market could be repurposed to treat bone cancers.

Working closely with Udo Oppermann, who leads laboratory sciences at the Botnar Research Centre within the University of Oxford, has been a key part of this journey. His extensive work in developing tool compounds has laid a solid foundation not just for discovering new therapeutics, but also for potential repurposing of drugs.

Chordoma seemed like an interesting disease to work on, primarily because not much is known about it. There's very little scientific knowledge on chordoma compared to the other more common types of cancer. Knowing that we have some preliminary data on cell lines, I wondered if we could make an impact in something that is under-researched — and here we are!

Why is the work of smaller charities important for rare diseases?

Small charities provide very targeted support and resources that are committed to a small network of researchers. A lot of major cancer funders, so far, tend to work on cancers which affect a larger population.

Rare diseases by their nature can affect a small percentage of the population, which leads to insufficient funding and attention from other major researchers and pharmaceutical companies. It is often difficult to get pharmaceutical companies interested in rare disease, but smaller charities fill this gap. They offer specialised funding to reduce the negatives about working with rare diseases.

Smaller charities can also be more agile and respond a lot faster to the requirements of researchers, along with the requirements of patients. You can also put researchers in contact with potential clinicians, which helps foster a close community. One of the biggest platforms for improving clinical research is collaboration, which is very important because no-one can work on their own anymore... those days are gone. Because of this, the community building aspect is invaluable with rare diseases.

Additionally, charities often spearhead support in innovation for research projects that larger funders consider too risky or too niche. The de-risking aspect is really beneficial to our work, as we begin with a set of potential hits from a drug screening approach and not much more mechanistic evidence. While the bigger charities would not fund this initially, small charities provide a solid foundation for larger studies to take place.

What do you wish that people better understood about research?

That it is really hard! It also takes a long time, and the expectations have to be tied to that. Everyone asks when the drug is going to come to market and when they can use it. Unfortunately, the answer is probably not for 5-10 years depending on modality. A small molecule is typically a very long development process, and costs billions!

Who do you admire in the history of medicine and why?

I admire scientists who have made significant contributions across a diverse range of scientific disciplines. My work intersects several fields, including computational science, biology, chemistry, physics and mathematics, and I have drawn considerable inspiration from some of the most eminent figures in these areas throughout history.

Amongst the renowned figures like Marie Sklodowska-Curie and Frederick Sanger, my greatest inspiration is James Lovelock. His pioneering work with Dimethyl Sulfoxide (DMSO) for cell preservation at Mill Hill in the 1940s laid the groundwork for its continued use today. Lovelock's innovations extended into chemistry, where he developed the electron capture detector (ECD), an instrument he built himself. This technology played a crucial role in the discovery of the depletion of the ozone layer, showcasing his profound impact across multiple scientific disciplines.

Beyond his contributions to chemistry and environmental science, Lovelock formulated the Gaia hypothesis, proposing that the earth functions as a self-regulating system. This groundbreaking idea led him to develop mathematical models elucidating the global ecological system, offering insights into how human actions can have both positive and negative impacts on the planet.

What do you hope to see in the future of chordoma research?

Ultimately, some better treatments. Currently, the treatment options available are inadequate, we need more progress to be made.

Some of the patient experiences we hear about are harrowing and the types of treatment that patients endure are really invasive. We need more optionality over those treatments, such as better radiographical approaches and better chemotherapies.

I go to a lot of the Bone Cancer Research Trust events and I find them very useful, particularly the patient conferences. I enjoy listening to patient advocacy stories, just to get a little bit more of an understanding, as you are often quite far removed from the work that you are doing in the lab.

Do you have a message for patients currently undergoing treatment?

Science does progress forward. Sure, it might not always zip ahead as quickly as we'd hope, but it's always on the move and we're constantly picking up new insights.

There's a bunch of promising therapies popping up for various diseases, and when you think back 20-30 years, the outlook for many conditions were pretty bleak. Fast forward to today and we're seeing some real game-changers, especially in the realm of genomic and genetic medicines. Fingers crossed this kind of innovation could make a big difference for rare diseases down the line.

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