E64: State of Oncology Report

Mary Parker:

I'm Mary Parker, and welcome to this episode of Eureka's Sounds of Science. Every decade, we learn more about cancer. And every year, new cancer drugs are approved. Oncology is an area of great concern to medical researchers. So where are we today when it comes to fighting cancer? Justin Bryans and Elizabeth Anderson both work in early discovery in our Saffron Walden facility in the UK and have agreed to lend their expertise to give me an update on oncology. Welcome, Justin and Elizabeth.

Elizabeth Anderson:

Hello.

Mary Parker:

Hello.

Justin Bryans:

Hello. Thank you.

Mary Parker:

Thank you both for being here. Can we start with a little bit of background on each of you? How did you decide to get into this industry? Elizabeth, you want to start?

Elizabeth Anderson:

Yes. I've always been involved in cancer research right from the very beginning when I left university and first started off in an academic environment, but worked quite closely with other drug companies, and then made the switch across to drug discovery many years ago and worked in large companies and small companies, working on all aspects of cancer research.

Mary Parker:

Do you find you have a preference between the academic and the more practical applications?

Elizabeth Anderson:

I like both, actually. So the academic allows you to get very deeply into a subject, but the drug discovery part means that you're developing. There's a more direct route to helping patients. Although I did work quite a lot in translational research beforehand and worked on bits of patients, as well as developing drugs to help treat their cancers.

Mary Parker:

Bits of patients. I like that.

Elizabeth Anderson:

Yeah.

Mary Parker:

How about you, Justin? How'd you get started in your career?

Justin Bryans:

Well, I'd always had a fascination for medicine and I come from a medical family, but I've decided to do chemistry and use those skills to be able to make new therapies for patients. So I read chemistry, a fairly traditional route, degree, PhD, then postdoc, and then I went into the biotech sector, into pharma, and then I actually moved into a not-for-profit company.

And that's probably where I came across most of the impacts I saw with oncology, working with academics, many of them working in oncology. And I think there's one project that really sticks in my mind for obvious reasons, as you'll hear, is the fact that we were working with a biotech company to actually help them develop a cancer therapy. And they asked us to humanize an antibody, so to make an antibody more suitable for human treatment.

So we did that. I produced a very interesting effect in vitro and in vivo with this antibody. We heard nothing more about it for a few years, and then a press release came out saying that this antibody, which was the one that we'd had a hand in, was creating very interesting effects. And that antibody had got a name, and it was called pembrolizumab.

So we were one of the companies that were starting out in the immuno-oncology space. So really fascinating to get into that space. So I've been hooked ever since on trying to find new treatments for patients in all sorts of therapy areas, including oncology.

Mary Parker:

That's amazing. That must've been really cool to experience.

Justin Bryans:

Absolutely. At the time, it was another project, another interesting project. But when you suddenly realize the enormity of the impact of what this treatment is doing to patients, it's a fabulous feeling to think that as a company we had a hand in this, albeit a small part of this whole process. But to be able to say, "We know we've had this hand in actually saving patients' lives," it's a tremendous feeling.

Mary Parker:

Yeah. Absolutely. So for both of you, how has our approach to cancer research changed in the past decade or so? So are we still focusing on radiation therapies, or have cell and gene therapies taken over? Sounds like you both have a broad range of research experience, so you'd probably be able to cover this really well.

Elizabeth Anderson:

Yes. So from what Justin says about pembrolizumab and the antibodies against this protein called PD-1, the big revolution over the past 10 years or so has been the introduction of immuno-oncology. So that's the understanding of how cancers become resistant or invisible to the immune system. So what these antibodies do is encourage a patient's own immune system to actually treat the tumors.

So pembrolizumab was the first or one of the first PD-1 antibodies. There's nivolumab. We've now got CTLA-4 antibodies. We've got LAG3 antibodies. And all of these antibodies are designed to enhance and prolong the patient's immune response against their own tumor. So this has been a massive paradigm shift, if you like, in the treatment of cancer, is that we're now seeing prolonged responses and even cures in patients who've got no hope before. So melanoma patients, very advanced melanoma patients are surviving for many years these days. And lung cancer, it's not perfect by any means, but it's been the biggest revolution in the past, I'd say 10, 15 years. And I've been working in cancer research for a long time.

Mary Parker:

Mm-hmm. And Justin, you agree?

Justin Bryans:

Yeah. Absolutely. I think I would definitely agree with the change that that's brought about cancer therapy. But I think there are other things which have also come to light. There's this idea of personalized cancer care, of trying to match treatments to specific patients and their specific tumor and their situation. I think it's really revolutionizing the way that we consider the patient, as well as the tumor itself and the disease. It's not just one disease. It's a whole range of different attributes you have to consider alongside the individual patient and their cancer.

And this runs alongside diagnostics. We have far better screening programs now, a much better understanding of genetics and how we can profile patients and their tumors. And you mentioned radiation. Of course, we've now moved into proton beam therapy, which is an alternative to standard radiation. It's a high energy, highly focused beam that actually really targets the tumor extremely specifically. And so you get very strong effects against the tumor without really risking too much impact on normal cells, which is where radiation has its issue. So proton beam, I think, is producing remarkable effects, particularly in some of the brain tumors we hear about in the news or young children who've undergone this therapy, which is remarkable, really. And that's how it's changing.

Mary Parker:

Yeah. When we talk about oncology, I'd like to specify we're not just talking about cures. We're also talking about improvements in treatment, improvements in pain management. What you said just reminded me, I had a friend who actually came on the podcast and talked about her cancer journey. She unfortunately died during quarantine. But before she did, they were giving her radiation, not in an attempt to save her, because she was terminal at that point, but just for pain management. But she couldn't get it in the same place twice was I believe what she told me.

So I think that's really interesting, because we usually thought of radiation as something that was trying to be curative and was harmful to the patient on the course to a cure. But I hadn't thought of it as a treatment for symptoms before.

Elizabeth Anderson:

Yeah. It's quite common, particularly for tumors that have spread to the bone and that can be very, very painful. Then a couple of fractions of radiation can really reduce that bone pain. It's a very useful part of the cancer treatment pathway, as well as being curative for some tumors. So radiation therapies combined with chemotherapy for treatment of rectal cancer patients, and it can be curative. So yes.

Justin Bryans:

We shouldn't, of course, forget surgery, which is obviously one of the mainstays of cancer treatment. And of course, there are big advances in the surgery field with the advent of robotics, which allow-

Mary Parker:

Oh yeah.

Justin Bryans:

... access where a surgeon can't actually stick his hand, very tight spots close to arteries or veins or close to spinal cord. We can now get robotics in that space. And the other thing we look at is fluorescent dyes, which can bind to a tumor tissue, and you can use them in the removal of brain tissue. So you can use these fluorescent dyes and the surgeon can look at the brain under a UV light. And they delineate the tumor margins so that ultimately the surgeon can be sure they're removing all of the tumor, but minimal removal of healthy tissue, which is so important in brain tumors to retain as much healthy tissue as possible. So there are remarkable changes, I think, over the last 10, 20 years.

Elizabeth Anderson:

Yeah.

Mary Parker:

Yeah. Absolutely. So what do you both see as some of our main challenges in fighting cancer? Justin, you want to start?

Justin Bryans:

Yeah, sure. I think from my perspective, one of the key issues is that cancer has this ability to metastasize. So it spreads. So if cancer didn't spread, it didn't metastasize, it wouldn't nearly be such the big issue that it is. But the problem is you get a tumor and it moves to your lymph nodes. It moves around your body. And suddenly, a patient can have many, many different tumors around their body, which then becomes untreatable in many cases. And it moves into the bone, into the brain.

If it didn't metastasize, if we could stop it from metastasizing, which is a real challenge, then I think that cancer wouldn't strike the fear into people that it does nowadays. And I still think, alongside that, we're still seeing patients at much too late a stage. We see patients routinely at stage three, stage four tumors. If we could catch them much earlier by diagnosis, using diagnostic tests which are highly sensitive and be able to pick up cancers at stage one or even before they've even formed a tumor themselves, then I think we'd have a much better chance of producing cures for people.

Mary Parker:

What do you think, Elizabeth? What are some challenges that you've seen?

Elizabeth Anderson:

Yeah. The challenges are resistance to treatment. And my own area, a particular tumor of interest is breast cancer. And there, you see that patients become resistant to whatever treatment you throw at them, particularly for hormone treatment in breast cancer patients. But you see it in lung cancer as well with the acquisition of new mutations in targets that evade the treatments that's been given.

So there's some fantastic papers that have just come out that plot the genetic changes in tumors throughout a patient's treatment journey, if you like. So they've had sequential tumor biopsies and look to see what happens. And I think basically it's provided proof that Darwin existed, but it is selection of the fittest.

Mary Parker:

Yeah.

Elizabeth Anderson:

So if you provide a selection pressure, like a treatment, then cancer cells are so plastic. They don't have the normal controls to prevent mutations, so they develop new mutations that mean that they've become resistant to treatment. And we need to know how to treat that. Do we give a massive, all encompassing treatment at the beginning, or do you try and manage the resistance as it comes along?

So with breast cancer patients, you can often cycle patients through different endocrine therapies. So they'll start with one, become resistant. You give another, they become resistant. And sometimes, you can circle back and start the same treatment again. So it's about perhaps managing the disease rather than trying to cure it.

Mary Parker:

Interesting.

Elizabeth Anderson:

But as we say, the cancers are incredibly plastic. They're able to mutate very easily. And of course, the cancer cells that have got mutations that allow them to escape treatment will grow and overtake the other cancer cells that are present. So it's an ever evolving landscape.

Mary Parker:

Yeah. Well, Justin, what currently are research priorities for oncology?

Justin Bryans:

I think for me it's really about better understanding the cancer pathways and what drives the tumor, both to appear, but also to grow, to spread, as Elizabeth said, what makes them from a homogeneous tumor into a heterogeneous tumor. So really, what drives this disease in the way that it does and what drives the resistance? So it's really better understanding of that.

And then exploration to the genetics of cancer and how that links into the genetics to the patient that the cancer is in, and how those two work together to create this devastating disease. And maybe better understanding of that will allow us to create new cures and new ways of approaching this disease and tackling it and eradicating it from that patient.

Mary Parker:

And what do you think, Elizabeth?

Elizabeth Anderson:

Yes. I think we talked about genetics of cancer and cancer pathways and drivers. And what we're starting to understand, it's not just mutations in the DNA itself. It's mutations or alterations in other pathways that might alter how DNA is transcribed and which genes are expressed.

So there's a whole area of what's called epigenetics. What are the other pathways that can alter gene expression or silence certain genes? So there's a massive amount of work that still needs to be done into drilling down, not only in individual mutations, but also how those mutations are transcribed and translated into proteins and what that means for the function of the cancer cells. So there's still a huge amount of work to be done.

Mary Parker:

And maybe this is a depressing question, but does it seem like a giant pile of work that we have the tools to do eventually, or are there aspects of that work that we still haven't developed the proper research tools to even look at?

Elizabeth Anderson:

Ooh, that's a good question.

I think we are developing the tools, and I think we may talk a little later about some of the artificial intelligence and machine learning aspects of research that are coming into research these days, the massive amounts of data that have been generated from looking at profiles of changes in gene expression. And we're developing the tools that we're still a long way from understanding all of the pathways, but we're certainly getting the tools into some kind of order. And with the advances in computing and machine learning and artificial intelligence, I don't doubt that we'll develop better tools and more powerful tools for looking at these very, very complex pathways and drivers of cancer.

Mary Parker:

Okay. Well, that's good.

Justin Bryans:

I think just to add to what Elizabeth said, for me, it does feel like a bit of a mountain to climb. It's a disease that every time you throw something at it that you think works, the disease seems to find a way to escape...

Mary Parker:

Yeah.

Justin Bryans:

... and keep on coming back and growing. So we have to work harder, faster, and smarter to be able to try and get ahead of cancer and to be able to deal with it. And there are some things that we may talk about later in the diagnostics field that might help us do that.

Elizabeth Anderson:

Yeah.

Mary Parker:

So Elizabeth, can you give me an example of one of the more promising breakthroughs in the past decade, just to pep things up a little bit?

Elizabeth Anderson:

We've already talked about the immune oncology field and the changes that have come about with the introduction of the antibodies that G up, if you like, your immune system. But the next generation of those therapies are what are called cellular therapies. So these are the CAR-T therapies. People may have heard about CAR-NK therapies. And this is where you take a patient's own T cells. So these are immune cells that you take from your patients. So the T cells are the cells that attack and kill tumors. But in most patients, they're not active for various reasons, some of which we don't know. So what you do is you take your patient's own T cells and you engineer them to recognize the tumor. So you introduce a binding protein that will bind to the tumor. So you're bringing the patient's own T cells to the tumor.

And there has been some absolutely fantastic responses and very durable responses in children with acute lymphocytic leukemia, for example, who'd failed all kinds of therapies beforehand. Patients with lymphoma, there's now some quite durable responses there. So CAR-T therapies are one of the more exciting introductions that they're not without risks. They do have side effects, which we're understanding how to manage, but revolutionary for some tumor types, better for blood cancer types. But we're still understanding how to use them for solid tumors. But that's one of the most exciting therapies.

And there are other approaches for bringing the patient's immune system into the tumor, so what are called bispecific antibodies, one arm of which recognizes the tumor, the other arm of which recognizes the patient's immune system, and they bring the two together. So there's a lot of exciting new data that are coming out, lots of new registrations with the FDA, which are based on these bringing the patient's immune system to the tumor.

Mary Parker:

What do you think, Justin? What are some of your favorite breakthroughs?

Justin Bryans:

So I couldn't agree more with Liz about the immuno-oncology space. To put it into context, I remember when I first heard about this, although the company I was in before Charles River, obviously being involved in a small extent with the pembrolizumab story. I remember I was driving home from work. It was a winter, dark wet night, I think it was, on one of the motorways in the UK. And there was a radio program, a podcast much like this on. And they had a cancer patient on there. And he told us this story about how he had stage four melanoma, so skin cancer. He had lumps all over his body, particularly his neck and his back. And he'd been asked in for a clinical trial on one of these new immune therapies.

And he went in with hope, but not expecting a great result. And he had his infusion. He went home and he said that he was watching television that very night. And his wife turned to him and said, "That lump on your neck, that looks a bit different. Has something happened?" And he said, "That's really odd you say that, because I'm itching all over. I don't know what's going on."

And he said within days his lumps had started to dissolve away.

Mary Parker:

Wow.

Justin Bryans:

They'd changed size, they'd changed color, they'd started to dissolve away. And within three months later, he had a scan and he was clear of cancer.

Mary Parker:

Wow.

Justin Bryans:

And that, to my mind, was absolute amazing moment to listen to that and realize the power of the immune system.

Mary Parker:

Yeah. Well, that also highlights the importance of clinical trials. My friend actually participated in the clinical trial after she knew she was terminal. And she knew that it wasn't going to really do anything for her, but she wanted to do something that would lead to data that would help other people. And so even at that stage, participating in a clinical trial like that can lead to such incredible results to help other people down the road.

Elizabeth Anderson:

Absolutely. And we're very, very grateful to those patients who do come onto the clinical trials, particularly the phase one clinical trials, where there's little hope that the treatment will work. But so many patients just want to be helpful to the next generation of patients and will participate in these studies.

Mary Parker:

So on the other hand, what don't we know? It's an impossible question to answer, but what are some of our oncology blind spots?

Elizabeth Anderson:

That's a bit like that Donald Rumsfeld question, isn't it? We don't know what we don't know.

Mary Parker:

Yeah. Exactly.

Elizabeth Anderson:

So one of the big issues is that not all patients respond to treatment. So you can have some patients or you can have a group of patients whose tumors look exactly the same in terms of some of the factors that we look at, but they don't respond in the same way. And we were talking about pembrolizumab earlier, this PD-1 antibody. And really, it depends on the tumor type, but really only about 30% of patients respond to the treatment. The ones that respond have fantastic responses. But there are other patients who show no response at all. And we don't fully understand why that is. We know that there are other cells in the immune system that prevent or that shield the tumors. There are other factors in the tumor environment that make it blind to the patient's immune system, but we don't fully understand what the interplay is between the tumor cells and the patient's immune system, and also the environment in which the tumor is embedded.

So trying to understand why some patients don't respond is very important. And this may come down to what Justin mentioned before, which was diagnostics about personalized medicine. At some stage in the future, hopefully we will have a way of saying, "Well, your tumor will respond to this," or, "It won't respond to that based on the factors that we see in your tumor or in the tumor environments."

And we see it. I've seen it a lot in breast cancers. Some patients will never respond to a treatment, even though their tumors look exactly the same as a patient who did respond. And we still don't fully understand why. But it probably comes back to the fact that tumors are incredibly plastic and can evade any kind of treatment eventually.

Mary Parker:

Yeah. What about you, Justin? What don't you know?

Justin Bryans:

Yeah. I think going along with what Elizabeth said, I think some of the issues really are about why some particular tumor types are so difficult to treat. Pancreatic cancer, esophageal cancer, incredibly difficult to treat. And I think that we don't really understand why they don't respond to treatment in many cases.

In some cases, it's because these tumors, such as pancreatic cancer, appears very late, because pancreatic cancer is a silent cancer. You don't really feel anything different until the tumor starts to metastasize and spread. This comes back to the point earlier. If it didn't spread, it wouldn't be such a problem. But the fact is that's when patients appear is because it's too late, it's stage three, stage four cancer. And by that time, it's gone too far and there's little that can be done.

So it all comes down to my mind about diagnosis and understanding how we can get to these patients earlier, and then we might have a chance against some of these very refractory tumors.

Mary Parker:

Well, speaking of diagnosis and other piles of data issues, we hear a lot about big data and AI. How are these changing the face of cancer diagnosis and treatment?

Elizabeth Anderson:

Shall I-

Justin Bryans:

Yes. You go first, Elizabeth.

Elizabeth Anderson:

Well, I'm going to talk about a very pragmatic approach to big data.

Mary Parker:

Good.

Elizabeth Anderson:

Which is about recording what happens to patients. So a paper appeared very recently in the British Medical Journal. And it was a study of 500,000 breast cancer patients treated in the UK, and it was about the changes in survival over time. And it's only been made possible because we've been recording data about patients forever. So all cancer patients are recorded on a database somewhere in the UK, and that's put together with the type of tumor and the treatment they had and the outcome.

So this analysis of 500,000 breast cancer patients has shown the massive changes and beneficial changes in five-year survival after being diagnosed with breast cancer. So since 1993, the five-year survival rate for patients who were diagnosed and treated in 1993 is of the order of, I think about 75%. Now, if you were diagnosed in the year 2010, your five-year survival rate is more than 90%, more than 95%. So the changes, and that doesn't really say why those changes have happened, but it shows that they are happening. And it's probably a result of increases in mammography, so screening for breast cancer so it's caught early, but also all of the improvements in treatment that we've seen over those years, so early treatment after surgery, new targeted therapies.

So these have all resulted in a massive increase in overall survival, and that's big data. But it's perhaps not big data as we think about it. But it's a massive achievement.

Mary Parker:

Yeah. What do you think, Justin? What do you think are the promises of AI?

Justin Bryans:

So I think in terms of genetics and AI, to start with genetics, I think we're getting a better understanding about what's causing cancer. We know there are some specific cancer genes, and we know that we can screen for these, and we know that if you do have one of these genes, then it allows people to make lifestyle choices about how they're going to mitigate against that cancer risk. There've been numerous people who've done this kind of thing.

I guess in the public domain, someone like Angelina Jolie, who was BRCA2 positive, she elected to have a mastectomy because she'd had close relatives who'd died of cancer. So we're starting to see those opportunities of making that choice to people, which I think is important.

And I think to extend that further, we're starting to understand what a genetic profile of a cancer risk looks like. And nowadays, for less than $200, you can send off a sample of saliva to one of these sites that look at your ancestry, and you can get a whole range of potential risk factors against certain diseases. Now, imagine if that happened for cancer and you could do that, and you could send it off and you would get your risk factors for certain types of cancers. It means that you can take control of your life and you can make lifestyle choices about what you might do.

For example, if you have a risk of lung cancer, well, for goodness sake, don't smoke, or at least if you do smoke, stop.

Mary Parker:

Yeah.

Justin Bryans:

Because these allow you to empower yourself. In terms of AI, I think we're starting to see some significant advances in the clinical situation. For example, AI has proven reliable, if not more so than a human reading scans of mammograms detecting cancer.

So we know this is a good thing to do, because first of all, it removes human error. So we're unlikely to miss anything. And secondly, machines can work 24/7. So it reduces diagnostic timelines for those women who come in and have mammograms. And obviously, there's that time between you've had the scan, when do I get my results? And I think for any disease, when you have a diagnostic test, it's that worry until you get the result. And we can reduce that time with much reduced error level. So I think these are where the AI is starting to have an impact, a real impact on patients.

Mary Parker:

Yeah. I can be a little bit of an optimistic skeptic sometimes, especially when it comes to things like AI. So I do feel like sometimes they over-promise what they can deliver. But the one area, like you said, that seems to be extremely useful and promising is analyzing those images, because you're right. For some reason, machine learning is really good at learning how to look at images and figure out what it's looking at, which is pretty awesome.

Justin Bryans:

That's exactly right. And of course, a lot of this is built on things like face recognition software, which around the world, all security services use and have used for some time, so have been developing this to recognize images. So repurposing some of these technologies for benefit in the human health situation, I think, is fantastic to see.

Mary Parker:

Yeah. A computer just sees data. It doesn't really know or care what the data is actually representing. It's just doing the math for you.

Justin Bryans:

That's exactly right.

Elizabeth Anderson:

Exactly. Yeah.

Mary Parker:

Yeah.

Justin Bryans:

But please, let there be a doctor at the other end who could [inaudible 00:35:03].

Mary Parker:

Oh my God, yes. Absolutely.

Justin Bryans:

... empathy and…

Mary Parker:

Absolutely need the human element, for sure.

Elizabeth Anderson:

Yeah. I was going to say that AI can do all these very rapid calculations and look for patterns and things. But at the end of the day, they can't really put the interpretation on the data. They can tell you what the data are. But what it means in terms of cancer treatment and cancer biology, I think we still need humans to be present.

Mary Parker:

Yeah. But any of the busy work that AI can take off the doctor's minds is a net gain for the patient.

Elizabeth Anderson:

Yeah. Yeah. Exactly. Yeah. Yeah.

Mary Parker:

So do either of you ever see a world without cancer?

Justin Bryans:

Oh, that's a big one. Rather depressingly, I think my answer is no. And I'll tell you why. It's because cancer is driven primarily by mutations in our DNA, and mutations in our DNA are hardwired into us because of our evolutionary process. So we make advances in evolution throughout history by someone creates a beneficial mutation in their DNA and they can suddenly do something or behave in a way that's beneficial. It's exactly as Elizabeth said earlier. It's about the Darwinian process. So I see that mutation is hardwired into us.

So I don't see a world without cancer, but I do see a world with better diagnosis, better treatments, and better life choices that we can offer to patients. So I do see the impact of cancer reducing, but I don't see a world without it.

Mary Parker:

All right. Do you agree?

Elizabeth Anderson:

Yeah. Sadly, I do agree. And in fact, there's an interesting piece of data that suggests that you accumulate a third of your lifetime mutations before you're even born, and then the other third in childhood and adolescence. So mutation comes along with DNA replication. It's inescapable. You can do a lot to reduce the effects of mutations. And one area that's possibly not as well looked at is prevention of cancer or strategies to mitigate the effects of lifestyles that lead to cancer.

So for example, for breast cancer, changes in lifestyle mean that there's an increase in risk factors associated with pregnancy and breastfeeding and menopause. So can we evolve some treatments that will mitigate the effects of those risk factors for cancer? So yes, I don't think we're ever going to be able to escape cancer.

And throughout evolution, you can see in fossil records that people had cancer even very early days. So it's here to stay, unfortunately. But with our better techniques, a better diagnosis and treatments, hopefully it will be a disease that people can live with rather than die from.

Mary Parker:

Yeah.

Justin Bryans:

I think that's the key point, is living with it, not dying from it. And I think we can take comfort and hope from look at the advances we've made over the last 10, 20 years, leaps and bounds in making improvements in treatment, in therapies, and in how we deal with this dreadful disease. So I'm hopeful for the future, very hopeful for the future, but I don't think we'll ever escape it.

Elizabeth Anderson:

Yeah.

Mary Parker:

All right. Well, that's fair.

Well, thank you both so much for joining me. This has been really fascinating. I appreciate your expertise on this topic.

Justin Bryans:

You're very welcome.

Elizabeth Anderson:

It's been a pleasure.

Mary Parker:

Thank you.

Elizabeth Anderson: 

Okay. Thank you.