From bases to breakthroughs: Editing cancer’s weak spots with CRISPR

BASE Rx is a spin-out company that leverages genome-editing technologies to identify single-base variants – changes affecting a single DNA nucleotide – to identify druggable vulnerabilities in cancer genes and predict DNA changes driving cancer drug resistance. By addressing the genetic basis of drug resistance, BASE Rx aims to tackle a major barrier to effective cancer treatment.

BASE Rx is a company based on technology that we developed at Sanger – myself and Dr Mathew Garnett. It stands for Base Editing Assessment of Somatic Evolution on Therapy, with Rx used as shorthand for therapy. It is a drug discovery company in oncology, and we use cutting-edge genome-editing technologies to map druggable pockets, which are specific regions on cancer targets that can bind therapeutic molecules. We take cancer cell models – including cell lines and organoids – mutagenise them using CRISPR technologies and then map pockets on cancer proteins at base pair resolution. This is all linked to sequencing, so we have been able to apply this approach at scale at Sanger. The ultimate aim is to use these screens to identify new drugs for cancer patients; drugs that will be less likely to succumb to rapid resistance in the clinic and so, have longer-lasting benefits.

We are using state of the art CRISPR technologies, like base editing and prime editing, to introduce thousands of mutations into these cancer proteins. Then, we count how many of them exist at the end of the experiment using next generation sequencing. So, we get a measure of drug resistance, which is a major problem in cancer treatment – some estimates suggest it contributes to as much as 80 to 90 per cent of cancer-related deaths¹ – and we also get a sense of which regions of a protein are important for cancer cell survival. It allows us to home in on those domains and those functional regions of the proteins without any prior structural knowledge. We can then prioritise those for drug discovery.

One key advantage of this approach is that we can investigate more than one protein at a time, as cancer cell survival is not only dependent on one protein in isolation, but a network of signals in complex signalling pathways. We can look at a whole pathway in a cancer cell and then make thousands of mutations in a single experiment. In one of our recent publications, we programmed in around 32,000 variants across 11 different proteins in the mitogen-activated protein kinase (MAPK) pathway² – a key pathway that controls cell growth and survival, and is frequently dysregulated in cancer.

While one aspect of our work is finding these novel druggable pockets, another is trying to retarget drug-resistant proteins. When drug resistance emerges in patients, we can rapidly find new ways to target that well-validated protein – now with a new mutation – as a novel drug target. This approach can lead to a second line therapy or a best-in-class therapy, which will also be effective in patients that relapse on their first drug. This is an important advantage in the arms race against cancer evolution.

The major aim is to extend the benefit from cancer treatments, meaning we can treat patients with drugs that will work better for longer, and also have follow up treatments for patients if they do unfortunately relapse on therapy. One of the key things that BASE Rx delivers is the speed – something that is really important in drug discovery. Since our approach is prospective and does not solely depend on the often lengthy and costly study of patient biopsies in clinical trials, we can accelerate the knowledge around drug resistance, and therefore, the development of next generation therapies. These have historically taken years or even a decade to make. Now, we can get that type of functional information within months, which I think is going to be transformative.

One of the key examples that I give is Imatinib, which is one of the first molecularly targeted drugs against chronic myeloid leukaemia or cancer in general. There is one dominant drug resistance mutation called T315I, that around 20 per cent of treated patients acquire, and then they are no longer responsive to treatment. It took around 10 years to go from the approval of Imatinib to the approval of a second line therapy called Ponatinib, which targets that drug resistant variant – and that is far too long for many patients. In that intervening period, thousands of patients would have not received a drug from which they could have benefited. That for me is simply an unacceptable situation, which we are trying to change. As a result, we prioritise cancer types with high unmet clinical need and a high incidence of drug resistance. These tend to be tumour types with high numbers of DNA mutations, for example lung and colon cancer.

I was previously a postdoc in Mathew's team at Sanger, and now I am a Cancer Research UK Career Development Fellow with my own research group within the Somatic Genomics programme. When I was a postdoc, Mathew and I realised that this technology and the screens that we were doing had a lot of translational potential, especially when we were looking at drug targets and drug resistance. There were some things that we knew we could not do within academia, but felt we could do within industry, that could benefit patients and the wider community. Specifically, making an impact in cancer drug discovery. Often the best way to translate research findings or a new technology is to drive the work forward yourselves; if you do not pick this up then it can be wishful thinking to expect someone else to do so. So, we started our own company. We were only able to do this down to the support of the translation team including some fantastic colleagues such as Dr Adrian Ibrahim, Dr Agnieszka Wabik and Dr Emmanuelle Astoul.

For me, Mathew was a huge help and an excellent mentor as he is already co-founder of the company Mosaic Therapeutics as well as a group leader at the Institute. He has a lot of experience in raising significant investment. We chatted about this at length, and both agreed that it would be a good complementary thing to do.

We were fortunate to first secure some funding from the translation office as one of their translation committee grants. With this, we hired a talented advanced research assistant, Yousra Belattar, who was working on that grant for a year to produce important proof-of-concept data. Next, we started to work with the translation office to write an Innovate UK grant – which are very competitive – and the application was successful. We were very happy to have got a Biomedical Catalyst award as it has enabled us to grow and incorporate the company.

We are only ten months in, so it is early days, but I have learned a lot, and it has been very rewarding – especially establishing a team of motivated people with a shared goal. We have spoken to many smart people who are not academics. It is very different to go to investment events rather than scientific conferences. It is a completely different ball game, and I have had to adapt to pitching to venture capitalists and pharma. I worked at AstraZeneca for three years before starting at Sanger, so I knew a little bit about industry, but I was very naive about the world of investment. It has been an interesting challenge to sell your science in a way that can feel slightly foreign from an academic perspective. But I have had a great team support within the translation office.

Another thing I have learned is how much of an iterative process it can be. Firstly, you go in with one idea, and then after several conversations with colleagues, the translation office, venture capitalists and pharma, you realise that perhaps what you thought was the best opportunity is not really the best opportunity or the highest value proposition. It seems a key quality is listening and adaptability, whilst always maintaining your key values. I think whoever you speak to has a slightly different opinion. Nevertheless, this has been an important process for BASE Rx and helped develop my thinking.

You learn a lot, and I have found it very complementary. I am very committed to my academic work, and I have just started out on the academic journey as a Career Development Fellow, and I hope to continue that for a long time. However, I have always been interested in entrepreneurship, so I actually started in the Startup School at the Institute some years ago. There are some things that work on a very different time scale in industry versus academia. You find that the timescales are very tight in industry and very focused. This means you become more goal driven, which is good for focusing a team. I think it has been beneficial for my academic work, because there have been things which we would not have been able to do – they both feed into each other and are synergistic. The workload is manageable as my colleagues are all motivated and excellent scientists, and I am learning how to delegate and manage a larger team – it has all been very positive so far. There are clearly certain lines between the work, like academic and industry, which are kept entirely separate. It has been invaluable to have Mathew, who has been through the process already with a much larger lab, as someone to guide me through the process.

Over the next five years, I hope that we can grow the company to achieve our goals. Ultimately, what is inspiring to me is that we can make a difference to patients’ lives. That is why I am doing this job; to make a positive impact. My lab is funded by Cancer Research UK, and they have a major focus on translational research that improves patient outcomes, and I am very much aligned with this vision. One thing that has inspired me is to see one of Mathew’s discoveries translated into a medicine. This has come from embracing new technologies, scaling them and applying them to important biological questions in genetics – true Sanger science. We will carry on embracing new technologies to improve our process to be at the forefront of change and drive innovation. Biotechnology is something that has always excited me and makes my job feel more like a hobby that I thankfully get paid for. In five years, I hope we can build a company where we are on our way to producing a drug that has the potential to go into patients. I envision we have got some backing, and we have made some discoveries which means that we are going to make a difference to patients. That is why we are doing this.

BASE Rx is using and developing some exciting biotechnologies. I think it is a very exciting time in cancer therapy more generally, as there are lots of targeted therapies that are coming through in some hard-to-treat indications that have not seen progress in decades. Therefore, I think this is a timely opportunity, and business sometimes comes down to simple things like timing. Currently we are seeking pharma alliances and venture capital investment.

We are also very fortunate that BASE Rx has just been selected for a spot on the highly competitive Accelerate@Babraham pre-seed support programme, led by the Babraham Research Campus. This presents an exciting opportunity to access expert guidance, tailored support and early-stage funding to help drive our continued growth.

In five years, I aim for our company to be growing – a nice place to work, where people are inspired, and we are making progress towards a new medicine. I would be very happy with that. Right now, I am just excited about the journey ahead.