Cancer drug discovery is fraught with challenges. In the battle to overcome these hurdles, Cancer Research UK (CRUK) has developed a strong translational agenda that brings together scientists from multiple disciplines to develop game-changing new therapies that could revolutionise patient outcomes.
Register for your free place at Drug Discovery 2019: ‘Looking Back to the Future’, 5-6 November 2019. To learn more, we talked to Heather McKinnon, joint head of Cancer Research UK’s Drug Discovery Unit at the Beatson Institute in Glasgow. In this blog, Heather shares her insights on the key challenges in cancer drug discovery and explains how CRUK is tackling some of the toughest problems head-on. We’ll also hear more from Heather at our upcoming Drug Discovery 2019 conference, where she will chair the ‘Oncology in Drug Discovery’ track.
Q: Could you tell us about the work of the Beatson Institute’s Drug Discovery Unit (DDU)?
A: At the DDU, our goal is to translate basic biological research into new treatments for cancer. This means we’re essentially bridging that gap between early scientific findings and validated therapeutic opportunities – or, if you like, the gap between academic research and pharma’s requirements. As such, we play a critically important role in CRUK’s translational agenda.
To succeed in our goals, we must collaborate with many different groups of scientists. Firstly, we work closely with the researchers at the Beatson Institute, determining how best to take their discoveries forward. Secondly, we connect with many other centres, including those involved in clinical trials. Engaging with the clinic like this means we can develop a greater awareness of patient need, helping us direct the application of new research in the most effective way.
This ability to make the absolute best of basic research is what I most value about my work. I’m proud that we can ensure promising ideas are not lost but are ultimately translated into a real benefit to patients. Indeed, given CRUK’s ‘high risk/high reward’ strategy, some of our current projects have the potential to transform the landscape of cancer treatment.
Q: Could you tell us a little more about CRUK’s ‘high risk/high reward’ approach to translational research?
A: This comes down to one of the fundamental challenges of oncology research – the fact that the most profoundly important drivers of cancer are often the hardest to drug. Many pharmaceutical companies will therefore avoid working on such molecules because the risk of failure is so high. However, since successfully drugging these difficult targets could dramatically improve patient outcomes, the CRUK Beatson Institute has taken on this challenge.
It’s no easy battle, but we have great resources to work with. We’ve got access to state-of-the-art technology, as well as drug discovery expertise across a whole range of scientific fields. This breadth of knowledge is vital, as we can bring together experts from different disciplines – chemistry, structural biology, biophysics, imaging, cell biology, in vivo biology – and combine their insights. What’s more, by leveraging our close links to the clinic, we can broaden our knowledge base even further. Working together, we can achieve so much more than we could in isolation.
With this collaborative ‘team science’ approach, we’ve worked on some very challenging targets including KRAS. This is the most highly mutated gene in cancer, so successfully targeting it could have a huge impact on the treatment landscape. So far, it has proved extremely difficult to drug, but we’ve made exciting progress with a fragment-based approach.
Q: Please can you describe the fragment-based drug discovery (FBDD) approach, and explain its benefit for challenging targets?
A: The principle of FBDD is to screen low molecular weight compounds to identify novel binding sites. If a fragment binds, even with very low affinity, we use it as a chemical starting point to develop a compound that is more potent and selective.
The reason why this is so good for intractable targets is because we’re not always aware of their binding sites. Larger molecules may not bind, but small fragments can fit into shallow pockets and then be evolved into high affinity compounds using a structure-based approach. As such, we can now address hugely important targets that were previously labelled as ‘undruggable’.
Q: As well as the challenge of difficult targets, what would you say are the main hurdles facing scientists in cancer research, and how are people working to overcome these?
A: I’d say a major issue is therapeutic resistance. Currently, while many patients initially respond well to treatment, the long-term outcomes are not so positive. This is because resistant cancer cells persist, often in distant metastases, and this leads to clinical recurrence.
I think a key strategy to address this, as well as understanding the mechanisms underlying recurrence, will be combination therapy – using different treatments together to achieve the strongest possible effect. With this approach, we can reduce the likelihood of leaving resistant cells behind. Importantly, combinations need to target cancer cell vulnerabilities such as metabolic pathways or immune resistance, this way treatments can be more effective without exacerbating side effects.
Q: How do you think your experiences working in industry, academia and the charitable sector have benefitted your work?
A: My experiences in different settings have broadened my perspective on cancer research. I found that working in industry drove me towards a more translational mindset – since everything you do is focused on delivering therapies to patients, you can’t just do research for interest’s sake. Additionally, my work in cancer charities further strengthened my understanding of the patient perspective. This really brought home to me the desperate need to avoid side effects, and I’ve taken this awareness back to my research. So, when we’re developing therapy combinations, I always ask: will the patient cope with that? If side effects are too bad, it can have a real impact on the patient’s quality of life, and they might not be able to complete the trial.
Q: What advice would you give to researchers who are just starting out in this field?
A: It’s crucial to network and collaborate. Don’t work in isolation in a lab – speak to your peers in research and industry and find out what they’re working on. By developing a broader understanding of the translational landscape, you can gain insights that could help guide your work. And, as I said earlier, it’s particularly important to connect with the clinical community so you can build up an idea of the patient’s needs. When all’s said and done, researchers want their work to benefit patients, so it’s a matter of working out how to do that most effectively.
Q: How do you think attending conferences like ELRIG’s Drug Discovery 2019 event can help cancer researchers drive innovation?
A: These conferences give you a great opportunity to hear about innovative approaches to the really challenging problems everyone’s thinking about. If scientists share their insights, you can all learn from each other’s experiences. What’s more, these meetings give you that valuable chance to network and identify potential collaborators who could help advance your research faster. I’m certainly looking forward to ELRIG’s event in November!