Podcast: Changing the Playbook on Childhood Cancers

00:00:00 Daniel Levine

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00:00:07 Daniel Levine

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00:00:36 Daniel Levine

I'm Daniel Levine, and this is RareCast.

00:01:00 Daniel Levine

While there's been enormous innovation in the treatment of cancers over the past two decades, much of this has been focused on adult cancers.

00:01:09 Daniel Levine

Despite the advent of targeted therapies and immunotherapies, the treatment of childhood cancers relies largely on chemotherapy and radiation, both of which can create lifelong side effects in developing bodies.

00:01:25 Daniel Levine

And cancer remains the leading cause of death by disease in children in both the United States and the United Kingdom.

00:01:32 Daniel Levine

C-Further, an international consortium created by LifeArc and Cancer Research Horizons, is working to advance innovative treatments for childhood cancer.

00:01:42 Daniel Levine

It not only provides funding to discover and develop transformative therapies to treat these diseases, but also leverages its network to help advance promising therapies.

00:01:55 Daniel Levine

We spoke to David Jenkinson, head of Childhood Cancer Translational Challenge at LifeArc, about the approach C-Further is taking, the scientific and economic challenges of developing treatments for childhood cancers, and why new models for advancing these therapies are needed.

00:02:21 Daniel Levine

David, thanks for joining us.

00:02:23 David Jenkinson

It's great to be here, Danny.

00:02:25 Daniel Levine

We're going to talk about childhood cancers, the international consortium, C-Further, and how it's seeking to bring together researchers, clinicians, drug developers, investors, and others to create new cancer therapeutics for children.

00:02:40 Daniel Levine

Let's start with the problem you're seeking to address, though.

00:02:43 Daniel Levine

How big a disparity is there in the treatment landscape for childhood cancers compared to adult cancers today?

00:02:51 David Jenkinson

That's a really great question.

00:02:52 David Jenkinson

And I think, we need to start with acknowledging the fact that there are over 400,000 diagnoses of childhood cancer globally each year.

00:03:02 David Jenkinson

And that compares to about 18 million adult cancer cases.

00:03:08 David Jenkinson

So this is small in comparison to adult cancer, but it does remain the leading cause of death by disease in children, in children around the world.

00:03:20 David Jenkinson

And so, it is important.

00:03:22 David Jenkinson

And there is a disparity between the high income countries and the lower income countries, where in high income countries, maybe up to 80% of children survive their cancer diagnosis.

00:03:34 David Jenkinson

And that sounds great, but actually survival isn't necessarily everything because these children are, because of their treatments and because of the cancer itself, they

00:03:48 David Jenkinson

have to live with the effects of that.

00:03:51 David Jenkinson

So the effects of treatment and the effects of the cancer.

00:03:54 David Jenkinson

So childhood cancer survivors are about nine times more likely to die prematurely than peers.

00:04:01 David Jenkinson

And they go on to have a number of late effects, such as heart problems, fertility problems, hearing problems, as well as a higher potential to get a secondary cancer.

00:04:14 David Jenkinson

So there is a real problem.

00:04:17 David Jenkinson

and the problem can only be sorted by really addressing these very unique cancers in their own way.

00:04:25 Daniel Levine

The reason for the disparities can be complex.

00:04:31 Daniel Levine

The most obvious one would be a matter of economics, but why don't we see more drug developers pursuing pediatric cancers?

00:04:41 David Jenkinson

The problem is

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as you say, economics.

00:04:44 David Jenkinson

So many of the drivers for childhood cancer are quite unique and aren't seen in adult cancers.

00:04:51 David Jenkinson

Now there's a chance for us to really use the drugs that are being made in adult cancer and bring them to childhood cancer because the pathways that, the downstream pathways that drive the growth of the cells that are effectively the cause of the cancer are often

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or sometimes the same.

00:05:14 David Jenkinson

But the actual drivers of the cancer are regularly different.

00:05:20 David Jenkinson

Adult cancer, for example, is really a cancer of aging.

00:05:25 David Jenkinson

As we age, all of our cells go through replication and divide and create new copies of themselves, some more so than others.

00:05:38 David Jenkinson

But while they're doing that, they're copying their DNA.

00:05:41 David Jenkinson

And every time they copy their DNA, they make hundreds of mistakes.

00:05:45 David Jenkinson

There are systems within the cell that look for those mistakes and correct them, but they aren't foolproof.

00:05:52 David Jenkinson

And so every time a cell divides, there are changes.

00:05:56 David Jenkinson

And that's great in some ways, because without it, we wouldn't have evolution.

00:06:00 David Jenkinson

And, you know, we wouldn't have developed into the humans that we are today.

00:06:06 David Jenkinson

But it does mean that cells can become cancerous.

00:06:09 David Jenkinson

Now, childhood cancers are different.

00:06:11 David Jenkinson

Obviously, they haven't gone through that aging process.

00:06:14 David Jenkinson

So they're actually more about stall development.

00:06:18 David Jenkinson

So as a child is developing, we ultimately we develop from a

00:06:27 David Jenkinson

pluripotent stem cell.

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So a cell that can cause any type of cell in our body.

00:06:32 David Jenkinson

And our kidney cells, for example, are very different from our heart cells, which are different from our skin cells.

00:06:37 David Jenkinson

But they all come from a single cell initially.

00:06:40 David Jenkinson

And so as the child is developing, if there's a block in that development so that it can't get to a final cell that might stop dividing, that causes an outgrowth, which is a cancer.

00:06:56 Daniel Levine

I suspect some people may wonder why you just can't take an adult medicine and adjust the dose for a child.

00:07:03 Daniel Levine

I know there are some efforts to repurpose adult medicines for children, but what are the issues in treating a child with a cancer therapeutic approved for an adult indication?

00:07:16 David Jenkinson

So this is absolutely one of the ways that drugs are being developed for children.

00:07:25 David Jenkinson

But we know that isn't necessarily a successful way.

00:07:30 David Jenkinson

Part of the problem is that it costs a lot of money to develop these drugs.

00:07:36 David Jenkinson

And so to do that in a child, particularly where that drug is coming to the end of its protection, may mean that doesn't, it won't recoup the investment in it.

00:07:51 David Jenkinson

So that's one of the problems.

00:07:54 David Jenkinson

We all, but we do know that we can do that.

00:07:57 David Jenkinson

And in fact, that's what our current treatments are about.

00:08:00 David Jenkinson

They are the chemotherapeutics of the 60s, 70s and 80s that have been dosed into children.

00:08:09 David Jenkinson

And actually what we know in that case is that children can relatively take, can accept more of those drugs and are able to tolerate it better than adults.

00:08:20 David Jenkinson

So actually, we're really blasting these kids with these drugs.

00:08:25 David Jenkinson

Now, the problem is that those drugs aren't clean.

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They aren't only hitting one target and having one effect.

00:08:34 David Jenkinson

And because children have a long lifespan after the cancer, they develop late effects that adults wouldn't see because they maybe only have a 10 years of expected life after their cancer has been

00:08:50 David Jenkinson

has been treated.

00:08:52 Daniel Levine

You talked a little bit about the difference between adult cancers and childhood cancers.

00:08:59 Daniel Levine

I'm wondering what the implications are of that are mechanistically and in terms of targets that can be pursued.

00:09:08 David Jenkinson

Yeah, and that's a really good question because we're only just starting to get to the point where some of the targets that drive childhood cancer are being addressable by drugs.

00:09:20 David Jenkinson

So we've had the chemotherapeutic piece, which often was about damaging DNA or preventing a cell from a cell that's actively dividing from being able to do that.

00:09:34 David Jenkinson

And we've moved to the kind of more targeted approach where we're really going after, in the adult case, the drivers of that and often going after

00:09:47 David Jenkinson

catalytic enzymes and inhibiting their activity.

00:09:51 David Jenkinson

Now, that isn't often what is driving a childhood cancer.

00:09:56 David Jenkinson

There's a lot of fusion proteins, often with transcription factors.

00:09:59 David Jenkinson

So, you know, things that are binding to DNA and maybe have a pretty flat surface.

00:10:04 David Jenkinson

So it's a lot more difficult to bind a drug to them sufficiently well to inhibit.

00:10:12 David Jenkinson

And there maybe isn't even any catalytic activity to inhibit.

00:10:17 David Jenkinson

So what we're starting to see with developments like Protax and in some cases, approaches like gene silencing, siRNA and others, that actually we're now able to start to address some of those drivers of childhood cancer.

00:10:35 David Jenkinson

And so the science is kind of catching up with the developmental problems of the disease.

00:10:43 Daniel Levine

In the United States, the Research to Accelerate Cures and Equity for Children Act or RACE passed in 2017.

00:10:52 Daniel Levine

What effect has that had on changing the landscape?

00:10:56 David Jenkinson

So the RACE Act requires or allows the FDA to require development of pediatric cancer trials by companies developing drugs for adult cancers.

00:11:11 David Jenkinson

And

00:11:13 David Jenkinson

It's really forward thinking and forward-looking by the way that it does that on a molecular basis rather than in Europe, an equivalent would be where actually it's if the disease is present in childhood.

00:11:30 David Jenkinson

And so actually the FDA, the RACE Act is really forward-looking in that.

00:11:34 David Jenkinson

And it has definitely accelerated the number of trials, increased the number of trials and accelerated development of drugs for

00:11:42 David Jenkinson

paediatric indications, but it often doesn't bring them all the way through.

00:11:49 David Jenkinson

And certain of those drugs maybe are showing some promise, but then aren't pursued further.

00:12:02 David Jenkinson

And it doesn't overcome the issue such as the one we've just discussed, where you've maybe got a fusion protein, because those don't

00:12:12 David Jenkinson

those don't appear in adult cancers.

00:12:14 David Jenkinson

So there are some gaps, but it's definitely a step in the right direction, and something that we should welcome, we should, look to see continue.

00:12:25 Daniel Levine

You talked a little about the agents that are used to treat childhood cancers, but in general, what are the concerns about existing therapeutic options?

00:12:38 David Jenkinson

The existing options are really the ones that have been

00:12:42 David Jenkinson

the chemotherapeutics.

00:12:44 David Jenkinson

So standard of care for most childhood cancers is chemotherapy, radiotherapy and surgery, and it may be that you miss one or two of those out.

00:12:58 David Jenkinson

Really young children, radiotherapy is very detrimental.

00:13:01 David Jenkinson

You can developmental delay impacts on IQ and other things.

00:13:11 David Jenkinson

So

00:13:11 David Jenkinson

try to, clinicians try to avoid that.

00:13:15 David Jenkinson

But that's really what we have.

00:13:17 David Jenkinson

There are very few targeted treatments that are approved in childhood cancers.

00:13:23 David Jenkinson

And in fact, since between 2007 and 2022, only 7 treatments, targeted treatments were approved for children, specifically for children's cancers.

00:13:42 Daniel Levine

The C-Further Consortium is an international initiative that's trying to address the lack of targeted cancer treatments specifically developed for pediatric cancer patients.

00:13:53 Daniel Levine

Can you explain how this came about and what Cancer Research Horizons and LIFARC are?

00:14:00 David Jenkinson

Sure.

00:14:00 David Jenkinson

So

00:14:02 David Jenkinson

Maybe I'll take the second part of that first.

00:14:05 David Jenkinson

Life Arc, which is the organisation I work for, is a not-for-profit medical research organisation based in the UK.

00:14:13 David Jenkinson

We turn promising scientific research into impact for people living with rare diseases, including childhood cancers.

00:14:22 David Jenkinson

We form partnerships and provide funding and expertise to break down the barriers preventing

00:14:29 David Jenkinson

breakthroughs from becoming life-transforming treatments.

00:14:33 David Jenkinson

And we've been doing that for more than 30 years.

00:14:35 David Jenkinson

There's some real expertise within the organisation.

00:14:38 David Jenkinson

And in that time, we have delivered.

00:14:42 David Jenkinson

or contributed to five licensed medicines, including actually pembrolizumab, which is one of the, well, the world's leading cancer drug.

00:14:51 David Jenkinson

Cancer Research Horizons, who are our collaborators in C-Further, are the innovation engine of Cancer Research UK.

00:14:58 David Jenkinson

So Cancer Research UK is the largest charitable funder of cancer research in the world.

00:15:04 David Jenkinson

And Cancer Research Horizons take their funding

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and the inventions, the progress that's being made with that.

00:15:13 David Jenkinson

And their job is really to turn that into drugs that will treat people with cancer.

00:15:21 David Jenkinson

And over the years, they've been involved in bringing 13 cancer drugs to market, spinning out over 70 companies.

00:15:30 David Jenkinson

And through that, they probably contributed to over 6 million courses of treatment for cancer around the world.

00:15:39 David Jenkinson

So we came together about a year ago now to form C-Further because we both felt there was a real need in this space for bespoke therapeutics for children with cancer.

00:15:54 David Jenkinson

And so we formed this consortium and brought together both of our resources, including money as well as our own in-house

00:16:06 David Jenkinson

drug discovery capabilities to partner with the community on their great ideas to really push those forwards, remove the barriers to progress and develop drugs that can ultimately one day be used to treat children with cancer.

00:16:24 Daniel Levine

C-Further seeking to remove barriers to create a sustainable model to advance innovative treatments for childhood cancers.

00:16:32 Daniel Levine

What's the vision for doing that?

00:16:37 David Jenkinson

What we're looking to do is really build a consortium of like-minded organisations that feel that something needs to be done for children, specifically for children with cancer.

00:16:52 David Jenkinson

We, in doing that, we want to bring together resources so that we can build a portfolio.

00:16:58 David Jenkinson

We know that

00:17:00 David Jenkinson

We work in a space, drug discovery, drug development is a nutritional basis.

00:17:06 David Jenkinson

And so we know that much of what we do is not going to be successful.

00:17:12 David Jenkinson

And so we need to build a portfolio so that we can guarantee that success and really start to bring things forward.

00:17:20 David Jenkinson

But we also know that the pre-clinical work that we're doing within C-Further isn't going to be enough.

00:17:28 David Jenkinson

We

00:17:29 David Jenkinson

We won't have impact for patients until such times as a doctor can prescribe the drugs and a pharmacist can actually deliver those drugs.

00:17:39 David Jenkinson

And so we need to work out the ways to take it from drug discovery right through to market access.

00:17:47 David Jenkinson

And that can be really challenging with such a small indication as some of the paediatric cancers where there might only be a handful of children every year.

00:18:00 Daniel Levine

And how does this contrast to, say, a more traditional grant-making approach?

00:18:08 David Jenkinson

What we're really trying to do is bring together collaborations.

00:18:13 David Jenkinson

So in a grant-making approach, you would often find, because they're competitive, you would often find groups working maybe in a little bit more in silos.

00:18:25 David Jenkinson

So what we're trying to do is through a collaborative approach, really bring together the groups that can deliver on the problem.

00:18:34 David Jenkinson

That includes in-house resources.

00:18:37 David Jenkinson

As I said, between Cancer Research Horizons and ourselves, we probably have around 300 lab-based scientists that are drug discovery experts.

00:18:48 David Jenkinson

Bring those together with the academics who understand disease biology exceptionally well.

00:18:55 David Jenkinson

and have, in some cases, some of the drug discovery, drug development skills that are required.

00:19:02 David Jenkinson

And bring in others that maybe have some of the other aspects of drug discovery, maybe some of the PK, maybe some of the ADME, maybe some of the assay development aspects that really accelerate the process.

00:19:20 David Jenkinson

So it's not just giving out money.

00:19:23 David Jenkinson

and saying come back in two years time and tell us what you've done.

00:19:26 David Jenkinson

It's really working very closely with the academics or industry partners to progress a program so that we can accelerate new drugs for children.

00:19:39 Daniel Levine

What would constitute a project of interest to C-Further in terms of targets, modalities, or development stage?

00:19:49 Daniel Levine

And what do you

00:19:51 Daniel Levine

look for in projects, what criteria are used to evaluate proposals.

00:19:58 David Jenkinson

Really, we're working, as I said, in the pre-clinical space.

00:20:02 David Jenkinson

So for us, anything from a validated target, and now, you know, we can have a discussion, a whole discussion about what a validated target means, but something that has been shown to modulate the disease using either tool compounds or genetic methods,

00:20:21 David Jenkinson

And so the hit identification stage right through to late pre-clinical and really we're probably talking about pre-clinical candidate would be where we currently are looking to end.

00:20:36 David Jenkinson

So something in that space that we can add value to.

00:20:41 David Jenkinson

Modality wise, we're agnostic because of backgrounds,

00:20:47 David Jenkinson

We talk a lot about small molecules and antibodies because that's the expertise of a lot of the in-house scientists.

00:20:55 David Jenkinson

But we're also open to cell therapies and gene therapy approaches as well.

00:21:00 David Jenkinson

So very much looking to move things forwards as far as possible.

00:21:08 David Jenkinson

With regards to evaluation, we're also looking at, you know, what disease, what is the unmet need that we're trying to address.

00:21:16 David Jenkinson

We have done a piece of work around unmet needs and spoken to clinicians in the US, across Europe as part of COG, part of ITCC, so innovative therapeutics for childhood cancer, and part of SIOP, which is the European Society of Paediatric Oncology.

00:21:42 David Jenkinson

and ask them what they're unmet, what they feel the biggest unmet needs are.

00:21:46 David Jenkinson

And we've kind of taken that and we're working proactively with about 13 indications that have been identified.

00:21:52 David Jenkinson

But we also know there's unmet needs in all the other indications.

00:21:56 David Jenkinson

So we're open to any of those, actively looking for the ones that have been identified as a bigger unmet need though.

00:22:05 Daniel Levine

The current application deadline was set to close September 1st.

00:22:09 Daniel Levine

Is that still the case?

00:22:12 Daniel Levine

And what has the response been?

00:22:16 David Jenkinson

So the application, the previous application deadline did close on September 1st.

00:22:23 David Jenkinson

We're analyzing that right now.

00:22:25 David Jenkinson

And I can certainly talk about some of the previous deadlines.

00:22:28 David Jenkinson

But in reality, this is a rolling deadline.

00:22:31 David Jenkinson

We have to

00:22:33 David Jenkinson

sweep things up, but if people were to put an expression of interest in, we would assess it as soon as possible to make sure that we could give feedback quickly and people aren't sat in a hole for a while.

00:22:49 David Jenkinson

So we've, I guess for the first round, for example, which was run about a year ago, just when we launched C-Further,

00:22:57 David Jenkinson

We had a number, we had nine modalities across 10 indications and applications from 12 countries.

00:23:05 David Jenkinson

And that included academics and industry.

00:23:08 David Jenkinson

So, we're really open to everything and we're looking to, just understand what's out there, what the needs are and how we can help.

00:23:18 Daniel Levine

The initial funding is about $36 million of investment.

00:23:22 Daniel Levine

What other resources can you leverage beyond that money?

00:23:28 David Jenkinson

So not only do we have those in-house researchers who are able to do that drug discovery, but equally, are experienced drug hunters and therefore know what it takes to bring something forward.

00:23:45 David Jenkinson

But we also, between Cancer Research Horizons and ourselves, are able to tap into a world-leading

00:23:55 David Jenkinson

series of experts in the various diseases, in translational science, drug discovery and development.

00:24:02 David Jenkinson

So we can really bring together that consortium, that collaboration of people to push things forward.

00:24:10 David Jenkinson

We're also looking at other partners, bringing other partners on board.

00:24:14 David Jenkinson

As I said, this is, we want this to be a consortium of like-minded organisations

00:24:20 David Jenkinson

And we're looking at ways that others can, who share our view that there's a real need for bespoke therapeutics for children with cancer, looking at how we can bring those on board, how they can contribute, and how together we can really be better than the sum of the parts.

00:24:39 Daniel Levine

What happens to intellectual property created through the consortium?

00:24:45 David Jenkinson

So our model on that is that any background intellectual property sits with the organization that brings that forwards.

00:24:55 David Jenkinson

But there's a license, obviously, to be able to use that in the development of the therapeutic.

00:25:00 David Jenkinson

The foreground intellectual property sits with C-Further.

00:25:05 David Jenkinson

And we do that so that we are sure that we can commercialize that because ultimately we need someone to be able to sell

00:25:15 David Jenkinson

these therapies so that they become available.

00:25:19 David Jenkinson

And so that sits there.

00:25:21 David Jenkinson

But if we choose to stop, then that would be handed back.

00:25:26 David Jenkinson

So there are provisions for if we, if for whatever reason we feel that the programme is no longer progressible, any intellectual property that's been created during that process is handed back to the organisation, the applicant.

00:25:44 Daniel Levine

Given the recognition that patients don't benefit from therapies if they don't make it to market, what's the translational vision for what C-Further is doing?

00:25:56 Daniel Levine

Is there some plan to help advance promising candidates that might emerge from the work of the consortium or resources that projects can tap into?

00:26:06 David Jenkinson

Yeah, and this is at the forefront of our thinking.

00:26:09 David Jenkinson

As I said, there's no point in doing this if we can't bring them to market.

00:26:15 David Jenkinson

We could make some fantastic antibodies, some, shiny new molecules, but that's great.

00:26:20 David Jenkinson

That'd be a nature paper, you know, if we're lucky.

00:26:24 David Jenkinson

But that's not really having the impact we're out to do.

00:26:26 David Jenkinson

So we're absolutely looking at how to do that.

00:26:32 David Jenkinson

There's, we don't want to use philanthropic money where industry would be able to

00:26:42 David Jenkinson

invest.

00:26:43 David Jenkinson

And so we're always looking to see whether or not any of the targets that we are developing have a crossover into adult indications, or if there's an organisation out there that is interested in further developing that programme.

00:26:58 David Jenkinson

And so we would then aim to partner with them.

00:27:02 David Jenkinson

But where that isn't possible, we're also looking at how

00:27:06 David Jenkinson

we as either C-Further or as our individual organisations are able to take that forward.

00:27:13 David Jenkinson

So both organisations have expertise, experience in funding clinical trials and Cancer Research UK have their own drug development unit that have a lot of experience in taking molecules into first in man and developing those further.

00:27:33 David Jenkinson

So our aim is to

00:27:36 David Jenkinson

to work with partners to make this a sustainable package, and really to deliver three drugs into clinical trials every five years once we're up and running.

00:27:49 David Jenkinson

And then through doing that, we will, you know, looking to double the number of drugs that are approved by the EMA and the FDA over the next 20 years.

00:28:04 Daniel Levine

David Jenkinson, head of Childhood Cancer Translational Challenge at LICART.

00:28:09 Daniel Levine

David, thanks so much for your time today.

00:28:12 David Jenkinson

Thank you, Danny.

00:28:18 Daniel Levine

Thanks for listening.

00:28:20 Daniel Levine

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