The Melanoma Letter

A Fascinating (and Unexpected) Discovery: A Potential Cancer Fighter in the Skin Microbiome

Dr Richard GalloRichard Gallo, MD, PhD, is Distinguished Professor and founding chair of the Department of Dermatology at the University of California, San Diego. Dr. Gallo and his team recently discovered that a strain of common bacteria on the skin produces a chemical that can kill melanoma and several other types of cancer cells, while sparing healthy cells.

 Mark Teich, editor of The Melanoma Letter and scientific director of The Skin Cancer Foundation, interviewed Dr. Gallo about his discovery, the possibility of harnessing the chemical to prevent as well as treat melanoma, and the important role the skin microbiome plays in staving off infection and disease.

Mark Teich: Can you share a bit of your background and tell us how you made your recent discovery as an unexpected offshoot of your usual research?

Richard Gallo, MD, PhD: I’m trained as an immunologist and biochemist, as well as a dermatologist. I mostly focus on the skin, studying the field of innate immunity. More than 20 years ago, we discovered that mammals produce antimicrobial peptides on the skin, key products that kill bacteria.

About 10 years ago, we started looking at beneficial products that the microbes of the skin can produce, and we have found many. But the studies were always designed to detect anti-inflammatory molecules or those that could kill bad bacteria. This discovery of an anti-neoplastic agent came out of that research.

We were looking at many different kinds of bacteria from human skin, and we found there was something with unique chemical properties that was produced by one isolate of the bacteria Staphylococcus epidermidis (S. epidermidis). We were not biased toward anticancer actions; we were looking at antibacterial action. But when we discovered what chemical was responsible for the activity of S. epidermidis, the chemical itself dictated that we ask the question, “Could this be an anticancer molecule as well?”

MT: What was the chemical?

RG: This isolate of S. epidermidis can produce a chemical compound called 6-N-hydroxyaminopurine (6-HAP), which appeared to exert a selective ability to inhibit the growth of some cancers. Not all S. epidermidis makes this. It’s a very special strain with the genes that allow it to synthesize 6-HAP. Some people have it, but most do not.

When we looked at human skin bacterial genomic data with Julia Oh, our collaborator, we saw that about 20 percent of human patients have this strain of molecule with 6-HAP. This might mean that about one out of five patients could benefit — the lucky ones to be colonized by this particular strain.

MT: How exactly did you pinpoint 6-HAP, and how did you verify that it could work against cancer?

RG: When we first found there was biological activity in S. epidermidis, we collaborated with an excellent chemist, William Fenicle, who ultimately coauthored the paper with us. He helped us solve the structure of the molecule.

Once we solved its structure, we saw it had the potential to inhibit DNA synthesis. Then we tested it in a petri culture dish against both mouse and human cancer cells, and saw that by inhibiting DNA synthesis, it could stop the out-of-control growth of certain cancers.

But the real surprise to us was its selectivity: Lots of things can kill cells in a dish, but 6-HAP seemed to kill a number of tumor cells, without killing nontumor cells. It selectively killed transformed cells, those with a collection of mutations that no longer allow them to control their growth. But when 6-HAP was mixed with normal cells, it didn’t kill them.

MT: What accounted for that?

RG: It’s complicated. It turns out that the chemical itself could kill all cells, but the normal cells have an enzyme that deactivates it. The transformed cells, at least the ones we saw, lose that enzyme.

MT: It sounds like a normal immune function, where the immune system attacks diseased cells but not healthy cells.

RG: That’s what it looks like, like a detoxification.

MT: What was the next step?

RG: We needed to test the chemical’s overall toxicity, so we injected it at high concentrations into mice and found it did not affect the health of normal mice. It didn’t appear to be toxic. In the next experiment, we injected a mouse melanoma into a mouse and let that grow, then injected it with 6-HAP, and we could show that it would shrink the tumor without making the mouse sick. The tumor didn’t have the ability to detoxify the chemical like the normal cells in the rest of the body.

MT: How effective was 6-HAP at killing the melanoma cells?

RG: Well, using the chemical alone the way we did, injecting it alone, the tumor still grew, but I’d say it was something like 50 percent effective. Way up the road, one hopes that combining it with other treatments might greatly enhance those treatments.

But the next question, logically, was whether 6-HAP from bacteria that are simply growing on the skin, as opposed to the chemical being injected, could have an anticancer function. Since we had found it in a bacterium that naturally grows on the skin surface, it was not likely that we were testing its normal biological function by injecting it. We needed a strategy to test what it means if you have a bacterium on your skin that is making 6-HAP.

So, we did a controlled trial. We put the same number of bacteria on different groups of hairless mice, one group with S. epidermidis that could make 6-HAP and one with S. epidermidis that could not. We then exposed those mice to UV light, a carcinogen, for many weeks, causing the mice to make de novo tumors — newly derived skin cancers.

Every once in a while, we reapplied the bacteria to the groups of mice; since these were strains of human S. epidermidis that live on people, not mice, we had to keep repopulating them with the bacteria. At this stage, we were just testing these human strains in the animals. We tried to create a situation where we could accelerate tumor formation in the mice but set it up as if they were actually people with the kind of S. epidermidis that made or didn’t make 6-HAP. There proved to be a very big difference in the two groups: Those mice with the right bacteria, which made 6-HAP, grew very few tumors, far fewer than those with the same kind of bacteria that did not make 6-HAP.

That’s where we left it and what we reported on — the discovery of the bacterial strain with 6-HAP and its activity both in mouse cells and on human cancers in a lab dish, its innate activity in cells and its ability to be both therapeutic and potentially preventive, in an animal model.

MT: You mentioned that about 20 percent of patients might have this strain. Would there be a way to increase this percentage, somehow giving 6-HAP to more patients?

RG: It would be quite possible to do that. We are now testing a similar strategy, not against cancer but against inflammation and infection. We are putting a live strain of Staphylococcus hominis (S. hominis), with a beneficial gene profile, back on people, showing it can live there and have therapeutic effects.

But human studies of skin cancer patients will be very difficult to do. The first questions would be, if you happen to have the right type of bacteria living on your skin, do you have an advantage over those who don’t? Are you more resistant to skin cancer? Is there an existing association in humans between 6-HAP and skin cancer prevention, predicting that it has a protective ability? The mouse model predicts that’s the case.

There would be two ways of testing this. Unfortunately, considering the time course of tumors in a human population, doing the study prospectively would take 20 years. It would have to be a very, very long study involving many people. That’s tough to do. Another kind of study would be to look backward at people who get a lot of skin cancers versus those who don’t, and see if you find these bacteria more commonly in those who don’t.

If it proved to be the case that 6-HAP has a protective ability in humans, I could envision one day developing a therapy with it, perhaps using it as a preventive probiotic. First, there would have to be safety studies. It would be tough to find funding for it, because it would be very large, but we would love to partner with somebody to do it. With the right funding, we could go right to testing in humans today. It would be up to the FDA how to conduct such a study, but the best idea would be a series of increasingly larger studies, at first looking at smaller populations just to be sure it’s safe, then, when you’ve established that it’s safe, you would start testing bigger populations over longer periods of time.

MT: What form would the ultimate treatment take?

RG: You’d want a topical cream containing the right bacteria. You’d rub this in so the bacteria could live on the skin. You’d reapply it periodically, but eventually you might not even need reapplication — the preventive and therapeutic bacteria would just be living there.

MT: In other words, this medicine would literally be changing the patient’s skin microbiome?

RG: Exactly.

MT: As you know, the other story in this issue of The Melanoma Letter, by Jennifer Wargo, MD, and colleagues, focuses on the gut microbiome and what role it might play in patients’ response to melanoma therapy, specifically checkpoint blockade immunotherapy. Is there any congruence between the principles, approaches and goals behind gut microbiome research and your skin microbiome research on melanoma? How are they similar or different? Could one complement or interplay with the other?

RG: I certainly think so. The gut microbiome works on different organs and in different ways to help keep us healthy. Since the gut is the site of many ingested contents, including drugs, the idea that a gut microbe might help improve the way an orally administered drug works makes perfect sense.

With the skin, instead of examining feces, you can measure microbes right on the surface. And you can get to it much easier, just by applying a cream. It’s much more accessible and tractable for therapy. We have found a large number of bacteria on the skin in addition to 6-HAP that are beneficial, that help us stay healthy in many specific ways. We’re in clinical trials now that are showing great promise. We can develop drugs from microbes that live on the skin and deliver them directly through the skin. 6-HAP would be an example of that. Really, it would be just like treating people with microbes that live in the gut in humans, but with different means of drug delivery.

MT: Could the two be used in conjunction as a treatment?

RG: Why not? A multipronged approach would make a lot of sense.

MT: But could certain non-skin treatments reduce the supply of 6-HAP, interfering with the skin microbiome in a way that disrupts overall treatment effectiveness, just as certain treatments might disrupt the gut microbiome?

RG: In the skin-care industry, there are ways of treating the skin to maximize good bacteria over bad, just as in the gut. You can potentially have different diets for the gut microbiome, and we know that having a variety of microbes in the gut confers an advantage, as opposed to uniformity of bacteria in the gut, which is a disadvantage.

This is the same with the skin. At first glance, you would think that the skin microbiome would be greatly at risk of losing good bacteria because of all the antimicrobial soaps we use. Are these soaps sacrificing the variety of bacteria, losing certain good bacteria? Are we changing the skin microbiome for the worse? However, we’re learning that one of the main reasons we have millions of follicles on the skin is to hide all the good microbes. So, those good bacteria are not as exposed or at risk as much as you might think. They’re remarkably resistant, but nonetheless, you want to treat them nice. So, many companies are now working on ways of optimizing cleansing, moisturizing and other regimens that will optimize good microbes.

MT: Isn’t it often hard to know which bacteria are bad and which are good? How do you pick and choose which bacteria to leave and which to get rid of? And how do you isolate them from one another to deal with them differently?

RG: That’s exactly what we’re working on. We try to understand what’s good and what’s not so good. We’ve come to know a lot about pathogens on the skin, which cause disease, and we surely want to get rid of those. But we know far less about the benefits of other bacteria. We have to keep learning to be more selective in how to get rid of bad germs and pathogens, and to isolate and promote the more beneficial microbes. That’s how we found 6-HAP.

MT: How far off do you think we are from being able to put 6-HAP to use?

RG: I think it would be feasible to do next-step experiments in the next few years. I would love to facilitate it, and we might look into it in the future.

But cancer is not my immediate focus. We’re already in our third clinical trial testing applications of this same strategy with a different bacterium, but targeting other conditions, not cancer. Right now, my lab is focused on atopic dermatitis. We’re having success, and the treatment is showing great promise. All of this is happening today, not tomorrow.