Parker: Hello and welcome to Cancer Connections, a new podcast from Cancer Research Horizons, where we're going to get to know, to question, but also to celebrate the experts that are helping us to beat cancer. Cancer Research UK is the world's largest charitable funder of cancer research. As the charity's commercial arm, it's Cancer Research Horizons job to maximize the impact of that research by turning discoveries into treatments that reach patients with cancer. a huge part of that work happens through the Cancer Research Horizons Expert Network, a world-class community of scientific, computational, clinical, commercial, and investment leaders I'm Parker Moss. and I'm proud to be your host for this series. I'm really pleased that my guest today is Professor Simon Bolton. Simon is one of the world's leading figures in how our cells repair their DNA and what happens when that repair goes wrong in cancer. Simon is a senior group leader at the Francis Crick Institute. He's an honorary professor at UCL and he advises Cancer Research UK as their first chief translation officer, Alongside Simon's academic work, he's a company builder. In 2016, he co-founded Artios, and very recently he founded AltEx Therapeutics. Now, both of those were built around turning discoveries about DNA repair into new cancer treatments. That journey from fundamental biology. all the way to medicines is exactly what I want to speak to you about today, Simon. Thank you very much for joining us and welcome to the call.

Simon: Thank you Parker, it's great to be here.

Parker: All right, so why don't we start with the one note of the science that has driven you, Simon? So we know that our bodies have tens of trillions of cells that are in perfect equipoise. They're born and they kind of die in synchrony. Each cell knows when its time is up, when it will experience programmed cell death, but cancer breaks that pack, doesn't it? It switches off the signals that tell it to die in a sense, it kind of makes itself immortal. So that story of DNA damage and repair, from what I can tell, it has really been central to your academic story from the very, very start. Sam, can you reach back to your early career and tell us, what got you fascinated in this field of DNA damage and repair? And what are some of the high points of your academic career

Simon: Sure, thanks Parker. Yeah, I've been working in this field for 35 years now, a little over, and it's evolved considerably, but really the concept of DNA repair came to light with one of my scientific mentors. This was Thomas Lindahl, so in the 70s. Thomas made at the time this heretical discovery he was doing biochemical experiments with DNA in test tubes and discovered that it was unstable, was decaying, was prone to DNA damage and this was a very important discovery that led him to postulate that given that DNA is this hereditary molecule, the blueprint of all life. How could it be unstable? How could we have ever evolved if DNA was unstable? And of course, it turns out that because of the very chemistry of DNA and the very chemistry of life, the byproducts that cellular metabolism produces, DNA ends up being damaged all the time. It's quite frightening. if you think about how many different types of DNA damage, there are from base damages to really catastrophic situations where both strands of the DNA duplex is severed. So anyway going back to Thomas he postulated that we must have repair mechanisms in our cells that our DNA was not just going to be left to essentially degrade or become irreparably damaged or whatever. and he went on to discover the first DNA repair enzyme and fast forward I think nearly 40 years, he got the Nobel Prize for DNA repair along with Paul Modrick, Shinashe Sankar. And that basically spawned an entire field that evolved to the maturity it is today. And I suppose joined the ride in the mid 90s when I did my PhD with Steve Jackson. In Cambridge who was very influential in terms of my translational journey But I became very interested in that most severe kind of DNA damage that I mentioned where both strands of the duplex is severed now what's quite interesting about that is that These breaks are quite rare, but when they do happen, they're pretty severe and catastrophic for the cell because you can lose whole swathes of genetic information if you don't repair that damage effectively. It can lead to aneuploidy and I think this really points back to the original. summary that you gave, know, this link between DNA damage repair and cancer. Well, what happens is a lot of cancers have altered DNA repair mechanisms and that leads to accelerated mutation rates and that leads to variants that can be selected for during the evolution of the tumor. So it can acquire traits such as becoming immortal, acquiring the ability to divide without contact inhibition, essentially indefinitely, and to acquire the ability to migrate and move elsewhere. And that obviously leads to aggressive cancers that have metastasized. So all of that is underpinned by a mutational acquisition over time, which is part of the aging process anyway. But if you're DNA repaired effective, then of course that accelerates that. And so Great examples are, colorectal cancer where you have high levels of mismatch repair deficiency, microsatellite instability. Loss of that repair mechanism, you see very high rates of mutations that are required during the copying, the replication of the genome. Another one would be, I think, very familiar to people. even if they're not scientists, is we all know that UV and sunlight causes damage to our skin. And it does so by introducing chemical changes in our DNA. And if those chemical changes aren't recognized and repaired, they will lead to mutations and ultimately to skin cancer such as melanoma. So we have a mechanism that repairs those. There are many different types. So that's kind of how I got into it. It was super interesting. At the time, we hadn't fully appreciated the link to cancer. It was quite an esoteric field, it just wasn't totally clear but that quickly changed within the first decade that I was being a scientist.

Parker: Great. And that's what I wanted to ask you about next. you mentioned microsatellite instability, MSI, which is now a biomarker for one of the most successful drug classes checkpoint inhibitors. but these repair mechanisms go beyond biomarkers. They actually have become druggable targets. And it's clear that at some point you realize that. your research went beyond just understanding fundamental mechanisms of biology and you started moving from this voyage of curiosity to drug discovery. tell us when it became clear that these DNA damage repair mechanisms were druggable and how that inspired you to really pivot your career away from just studying pure biology into actually founding companies to drug these targets.

Simon: Yeah, so One of several very influential people in my career, and that was my PhD supervisor, Steve Jackson in Cambridge. during my PhD, where I was studying double strand break repair, in budding yeast, Steve came up with the idea of starting a biotech company to develop inhibitors of DNA repair enzymes. Actually at the time, conceptually, I really struggled with this. couldn't see where you would create the therapeutic window. We haven't appreciated at the time that there might be intrinsic differences between normal cells and cancer cells with respect to their relative dependencies on DNA repair mechanisms. But Steve had this vision and for those of you know, Steve is incredibly driven and motivated and he ended up founding a company called QDOS and they went on to develop a number of different DNA repair inhibitors. But it wasn't until two landmark discoveries, a common discovery that was made independently by two groups. One was by Steve Jackson and Alan Ashworth and the other was Thomas Halliday and Nicola Curtin. And they discovered that an inhibitor of a DNA repair enzyme, was called PARPs or poly-EDP ribose polymerases, created an incredible therapeutic window whereby normal cells are essentially resistant, cells that are deficient for BRCA, which happens in a lot of breast and ovarian cancers, are exquisitely sensitive to these PARP inhibitors. Now, The mechanism by which you get synthetic lethality is still debated 20 years later. There are a number of camps, but what is true is that these are very, very effective molecules. And QDOS had developed a molecule that ended up being acquired by AstraZeneca. and being taken all the way through to clinical registration. was the first parpenibular to be clinically approved and that is a laparib or linparz, And that has now been used to increase the life expectancy of many, many, people around the world with BRCA mutations and actually more broadly. the process of a molecules recombination, is essentially the accurate mechanism of double strand break repair. Simplistically, it's a photocopy mechanism whereby a broken DNA molecule uses an identical sister chromatid as a template. So that was really inspiring because it revealed this therapeutic opportunity, this vulnerability of certain DNA repair deficient backgrounds. that could be exploited therapeutically. So that's stuck in my mind. But when does the opportunity arise? It can't be planned. It happens often serendipitously or completely by chance. But I think what it did trigger in my mind is just to evaluate the science that we were doing in a slightly different way. is this actionable, right, what we've discovered? And for many years, we didn't find anything that I felt had real traction. Until probably around 2012, we made the discovery of a chromatin remodeling enzyme called ALC1, which stood for amplified in liver cancer. It becomes an addiction in a lot of liver cancers and other cancer types as well. And I thought, hang on a minute, If we could make an inhibitor of this, maybe this could have therapeutic opportunity or therapeutic value. And so we started to engage actually with cancer research technologies, the commercial arm of Cancer Research UK. which has now become Cancer Research Horizon, So they were very helpful in advising, you know, for an academic who had never done this before, You end up pull down a rabbit hole that you're just not familiar with. There's a lot of different skills. I've been trained to be a geneticist, molecular biologist, and over time, quite an understanding of biochemistry, biophysics, genetics in different organisms, that kind of thing. But what I'm not trained to do or wasn't at the time was to do much more milestone driven science, which underpins the commercial translation, How you take a target, which is often genetic. How do you then create a small molecule or a biologic or a cell therapy? And how do you then develop that into something that has commercial traction? And it's a very different skillset. And that was the scary thing for me.

Parker: Yeah, that's exactly what I wanted to ask you about next. just tell us a little bit about what RTOS and Alta X are trying to achieve and then go into a little bit more detail about the different pressures and the different skills that you have had to acquire and how you've achieved that. Because you know, in the first part of this conversation you've really come across as a classic deep pure scientist, but you've had tremendous success now, two times in a row. of bringing funding to new companies recognized not just in the UK but internationally by some of the smartest investors. So what what did that journey take?

Simon: it comes back to this ALC1 work that we were doing with cancer research technology. We started to develop small molecule inhibitors based on biochemical assays that we'd published in a science paper at the time. And cancer research technology, we're also working with Jeff Higgins in Oxford who discovered that you could radio sensitize tumors through genetic depletion of an enzyme called pol-theta, we had some very early hit chemistry that we were progressing. And I believe it was Kate Bingham from SV Health Investors, a real visionary. She was instrumental in making the suggestion that, given the success of Kudos, there was space to start a second DNA repair company. And we, pitch the science to her and to several other investors ARIX Imperial Innovation, Sixth Element, AbbVie and Merck. And we ended up pulling a syndicate of investors together. And it was actually super early. I mean, this was obviously over 10 years ago now. And the bar has been raised considerably in terms of what you need to really get. to a level where you have opportunity for substantial investment. But we raised a substantial Series A, certainly for what we had at the time. And Neil Martin came in as the CEO and Neil was instrumental because he's a truly outstanding team builder. He'd done this at Kudos. He become CEO at Mission Therapeutics, Steve Jackson's second company. And so a number of us started Arteos. uh, initially virtually, and then developed the company into it to what it is. where the direction of travel has taken us has been to develop, a late stage clinical portfolio. This is now 10 years old, it's still privately financed, which is really quite unusual for any biotech, nevermind a UK startup, that has two assets, a pol-theta inhibitor, which I briefly mentioned, and an ATR kinase inhibitor We've solved the ATR toxicity problem. in a way that a number of other big pharmaceutical companies missed. And they are now fast-track designated by the FDA. They're in phase two, with a view to undergoing a pivotal phase three through to registration in the near future. So super exciting, But alongside all of this, I was very fortunate that I could do both. I could have two hats. I was able to work with Arteos as their advisor on strategy. So as you kind of mentioned Parker, I'm a more fundamental discovery scientist. So I could really impact and influence how we thought about targets and you know, the portfolio that we build, how does that fit in? the targets differentiated from one another, which is super important? How do we de-risk the portfolio? What are the new targets we can bring in? And this kind of plays to your point about advice to others. to start a company, you can't have a single asset. It's too risky for investors. So you need to think about a portfolio. Could be a platform play where you have a number of opportunities in a particular indication. And given that attrition is, let's say one in 10 might make it to the clinic. and one in 20 have a shot at actually getting through to registration then you need to have a number in play in order to de-risk the company.

Parker: just tell us a little bit about Alta X

Simon: Yeah, And so in parallel, I continue to run my group at the Crick and this has been great. the Crick's an amazing place to do science. We're really privileged to be here. get a lot of support. Altex came about through our interest in a process called alternative lengthening of telomeres. And it's essentially a process that repairs and maintains our chromosome ends. And this is a critical vulnerability to cancers. They need to divide indefinitely and maintaining their telomeres is something that's absolutely essential for all cancers to achieve. So it turns out that ALT is used in about 10 to 15 % of all cancers. That sounds like a small number, but it's millions of cancer patients. that are diagnosed with an alt cancer globally each year. So, you know, it is a significant unmet need. There are no precision oncology medicines. And we discovered through fundamental science ways that you could potentially target this. So initially we found genetic vulnerabilities in alt cancers and then we were able to de-risk those with chemistry. And so Alt-X was founded Earlier this year, we received funding largely through Syncona, but also through Cancer Research Horizon's Translation Fund, and also a philanthropic fund that we have here at the Crick called the Banton Fund. And we're now expediting drug discovery on a number of alt targets, which is super exciting. And that's, you know, been my journey and it's been fabulous.

Parker: It's an incredible journey. And I wish you the best of luck with all techs. this whole telemeric function is of particular interest to me because I know that not only does it have great adult significance, but some of the major pediatric cancers are also really driven by telemerit lengthening. It's super exciting. And in a sense, I think in that long answer, you validated the purpose of this. Whole podcast series, which is called Cancer Connections. it seems to me that whilst you are still very much an academic, you've been talented at finding and building connections with some of the other brilliant people in our ecosystem. You mentioned Kate Bingham, who we all know and love. But also, of course, Syncona, who are one of the great UK funders. So it really does sound that building teams, building connections with people whose skills complement yours has been a major part of your success story. a quick fire one. If you were speaking to an early stage scientist they've made a discovery, they know they're gonna get a high impact paper out of it, how would you advise them to decide whether to move on and write the next paper or whether to put those years of commitment into trying to translate this discovery into a drug?

Simon: I mean, it can be quite daunting, right? Because I think as I alluded to in a previous answer you know, I'm trained first and foremost as a discovery scientist and there are very different skill sets that you need for that translation, innovation journey. But increasingly, This is becoming a significant initiative from our major funders from Cancer Research UK, UKRI, Welcome, et cetera. And they're putting in place training schemes that can help educate academic scientists on what it is that they need to do. I would advice first and foremost to identify people who, like myself and an increasing number of us, who have taken that step from academia into that kind of translation journey to get some advice. Because I think you need to build an understanding of the process that you need to go through. That might be through your tech transfer office or translation initiative run by your university or institution. So I think getting some understanding of what that might look like would be a good starting point because it's a different language and navigating that is challenging. There's also an increasing number of accelerator programs from these different funders that are designed to provide some level of support. Cancer Research Horizons has a translation fund, which essentially helps you take that step from. discovery towards something that is more likely aligned with something that could receive some level of investment. cancer research horizons, cancer research UK would be another very good, port of call to, engage with, to find out what that journey might look like. and it's about, as you said, teams of people. So then about building a network of people. who can help you and a lot of these organizations can start putting you in touch with the right people. So I think that's a really good starting point.

Parker: So that's great advice for an early career researcher. I'm now love to hear your advice to the system at large the UK health ecosystem. You've clearly benefited from not just a network of experts, but some of our best funders, but we have to acknowledge that I think nine out of ten of all biotech dollars are going into US biotech. So what do you think is still missing in the UK ecosystem to help? you know, translational innovators like you get off the ground. What would you like to see more of in the UK?

Simon: Yeah, I'd like to see our funders to be more joined up, right, in the sense that we have great science. mean, we punch way above our weight on a global scale in the UK. there are many amazing discoveries that are made here that I believe don't get picked up effectively by the commercial engine So I think you know, one government initiative would be to try and coordinate the big scientific funders, bring in pharma, bring in some of the great investors that you've mentioned. and try and come up with a coordinated strategy to really help nurture that talent. And there are initiatives that the Pulse program, Nucleate UK, for example, providing a framework of support to early career. scientists who want to take that entrepreneurial route. But of course, you need money. This is an expensive business. It's considerably more expensive than running an academic lab. And I suppose plays to the teams of people you need to pull together to be effective. It could be joined up and I would really like to see the government taking a big initiative on this to pull all of these resources that we have in the UK together in coming up with a coherent strategy. that would help everybody. At the moment I see it as a little bit piecemeal. Each of these organizations have their own way of working and it's quite daunting to somebody who's trying to get into this to know which way to go. Obviously if you're in cancer, which is what we're in, there is a very clear direction of travel you would go with Cancer Research UK, Cancer Research Horizons. But we need to think more broadly, other modalities, other disease indications. It's not just about cancer, neurodegeneration, infectious diseases, and rare diseases

Parker: I'm glad you've mentioned these other modalities and other disease groups. It's such a thrilling time in cancer at the moment with all this innovation in in vivo expression and the dawn of personalized cancer vaccines and new methods of manufacture. outside of your area of DNA damage and repair, what is the one experiment that you would most like to see solved in your lifetime?

Simon: Sure. the thing I would like to see by the end of my academic career would be a better understanding of disease resistance. are a lot of lessons to be learned about this from, for example, the HIV, AIDS, epidemic, right? If you look at, the successful drugs that were developed by Gilead and others, What was very clear is that a single drug will not suffice. You need several to mitigate the ability of viruses to acquire resistance to a particular drug. so you need to hit the, HIV with three different drug modalities, designed to affect the biology in a number of different ways. And then you can get sustained responses. The same is true for other diseases, Particularly cancer. you the bar is so much higher, it's so much more complicated because there isn't one route to cancer. It's very much a disease of the individual. There are obviously common themes between individuals, but then you get sub-counter types, We've talked about BRCA cancers. There are multiple flavors of breast cancer, That have different responses to different drugs, but ultimately we're gonna need a repertoire of... drugs to deal with this. And I would like us to understand disease resistance in much more detail. Because I think that lies at the heart of actually getting durable responses So a single drug is great, but it's not the answer long term.

Parker: We're perhaps that's a good place for me to end by just asking you one final question. I'd love to ask you if you can think of anyone in our cancer ecosystem. It doesn't have to be a scientist, this could be an investor or a leader in industry, but someone that you think has a great story to tell. who would you like me to speak with next?

Simon: Well, we've already talked about Kate Bingham, she was the obvious one that comes to mind. I think she's probably the top of everybody's list. But, you know, it would be really interesting to get someone like Gonzalo Garcia from Sincona. a very smart guy, an investor, who's really gets into the science. I mean, one of the things I've learned is just how smart investors are. they learn the biology and the science. They ask really probing questions. And Gonzalo is a great example who cares deeply about the science as you would because if you're to make an investment you really need to get deep into the weeds.

Parker: Love that. And I love that such a deep fundamental scientist picks two investors, And with that, Simon, I would really love to thank you for being such a great guest and for sharing so warmly your incredible experience. thank you for listening to Cancer Connections If you like what you've heard, Please subscribe wherever you get your podcasts. And if you've got any questions or feedback I'd love to hear from you. I'm Parker Moss and until the next one, goodbye.