Doctor Heath Skinner talks about how personalized radiation can boost cancer survival.
I wanted to ask you a little bit about what you and your colleagues are investigating.
SKINNER: So, what we’re looking at are ways to try to predict how patients will respond to the most standard of treatments, the most standard curative treatments, in solid tumors. And typically speaking, the number of ways that we can predict how patients will do are actually very few. We have very few known drivers within a tumor that’s going to tell me, as a doctor, how the patient is going to do with our standard therapies. The best biomarkers that we have are, unfortunately, in situations where we can’t make the tumor go away and never come back, situations where we just give a drug. What we’re looking for are biomarkers for radiation, and radiation is one of the most common forms of curative therapy for solid tumors. Indeed, more than 50% of all patients with solid tumors in the United States treated with curative therapy are treated with radiation. So our study was looking at tumors, starting out with tumors of the head and neck, and seeing if there was a simple common biomarker that we can look at that can tell us which patients are going to do well with radiation and which patients need something extra. And what we found when we looked at those tumors are mutations in two genes that, to my knowledge, have never been clinically linked to radiation response. These two genes are named caspase-8, and then there’s two other genes that are really similar to one another, CBP and P300. Mutations in either of these genes are relatively common in head and neck cancer as well as other solid tumors and associated with poor outcomes following radiation therapy.
Can you tell me how you went about finding those mutations? Was this a study in a lab rat model?
SKINNER: These were actually in human tumors. So, we took human tumors and looked at mutations within those tumors, and that’s how we found them. And that’s how we could link mutations in these tumors with clinical outcomes in patients. Moreover, we didn’t just study head and neck cancer, we also looked at a couple of other common types of cancer that are treated with radiation, lung cancer and cervical cancer. And in both of those cancers, at least mutations in those two genes, CBP and P300, were associated with worse response to radiation and worse outcome, worse survival.
So now that you have those mutations targeted, what’s the next step? What can you do?
SKINNER: So, the next step we actually did in our study. So, what we did is we looked at tumors with those mutations and we broadly screened a large number of things that we can target in the clinic using drugs to find out which of those things, in combination with radiation, would specifically target these therapy-resistant tumors. And what we found was that a common class of drugs that are being investigated for clinical use, the histone acetyltransferase inhibitors – big word – but it basically attacks the function of the genes that are mutated. If you combine that with radiation in the mutated tumors, you have these dramatic responses – some of the best responses I’ve ever seen in animal models. So that was the next step, and that’s what we’ve done. The next step after that is can, we take that observation and then move that into clinical trial?
Now you said the drug is investigational, so is it a matter of waiting for that drug to be approved for use or can you move this into clinical trial in humans?
SKINNER: Well, that’s the goal. The goal is to concurrently move that into clinical trial use. And it’s being investigated, but it’s being investigated in the context of performing clinical trials to make sure it’s safe and to look for its effectiveness as a standalone agent. Sometimes the challenging parts with radiation therapy trials are that you’re limited in what drugs that you can combine with radiation because sometimes a drug that works really well on its own or a drug that works really poorly has differing responses when you combine it with radiation. And that’s important for people to know because radiation is such a common form of curative therapy. And we are way behind the times in regards to things that we combine with radiation to make radiation work better. And that’s, unfortunately, a function of a lot of different things. It’s hard to do radiation therapy clinical trials. We do quite a few at our institution, thankfully; but it’s hard to get those done. It’s super important because we have so many patients in the United States treated to curative intent using radiation. That’s one thing I do kind of want to bring home is that this kind of research in general is important because it affects so many patients.
People have heard of immunotherapy. We’ve heard of chemotherapy that’s personalized. Is this personalized radiotherapy is? Is it a lot of like having immunotherapy at your hands or no?
SKINNER: So, it’s a little different in a couple of respects. What I would envision is that you look at a tumor, you analyze it and you find key things within that tumor that, number one, make it more resistant to radiation and then, number two, hit those things and combine that with radiation. And that would make it truly personalized. This patient gets radiation with drug X, this patient gets radiation with drug Y. Moreover, potentially even bigger consequences, one of the problems with radiation is that it has side effects and has toxicities, and those toxicities last lifelong. So, if we can combine a targeted agent with radiation to make radiation work so much better on the cancer cells, maybe we can pull back the radiation dose, make it less toxic while still having really good effectiveness and making cancer go away and not come back.
Doctor, you talked about the fact that this is for solid tumors in not only head and neck, but lung and some other cancers. Why is that so important right now for doctors to have some of these other avenues?
SKINNER: So I think it’s important because we’re realizing that, although cancers differ by site, where they originate, head and neck, lung, breast… they also differ based upon their biology. Which is to say that, if you took a tumor from the head and neck and a tumor from the lung, some of those tumors may have more similarities between them than they would with other head and neck cancers or other lung cancers. So, it’s really important to be doing some form of molecular analysis on these tumors because site alone is not enough. Stage alone, meaning how big the tumor is, how far it spread… that’s not enough either. Tumors behave very differently irrespective of clinical stage, irrespective of site. And the more that we know about a tumor, the more that we know about its molecular subtype, the more that we know about what happens within the tumor, how the immune system responds to the tumor, the better we can treat it.
What’s the potential impact of this finding?
SKINNER: So, I think a potential impact of this finding is a few fold. Firstly, we’ve identified and what is – in what my belief is a reproducible, relatively straightforward biomarker of response to radiation in multiple tumor types. That’s number one. And number two, it’s targetable. So, the goal would be a prospective trial looking at patients that have these alterations that I’ve described and combining with the drug plus radiation. Or even, taking a step back beyond that, just doing a prospective trial of looking at those patients that are predicted to do poorly, maybe increasing the radiation dose to a smaller area to see if that helps. So, I think that there are a number of different ways that we can integrate this into patient care to improve survival, to improve responses, to improve outcomes for a large group of patients, potentially across disease sites.
How long could it be before we could see this in clinical trial?
SKINNER: So, if we’re talking about looking at it prospectively in regards these mutations, that would be within a few years, I think. If we’re talking about linking the drug to the mutation, that might be a little bit longer.
Is there anything I didn’t ask you, doctor, that you would want people to know?
SKINNER: I think what I want people to know is that we are diligently working to try to personalize radiation in a way that’s never been done before to improve outcomes for our patients, to make the experience better. And it’s critically important because, unfortunately, sometimes radiation doesn’t get as much attention as some of the other types of therapeutics and yet it is part of the curative backbone of a huge number of patients. So, I think it’s critical to bring across.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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