University of Cincinnati professor of dermatology, Zalfa Abdel-Malek talks about a new way to protect your skin from skin cancer.
Interview conducted by Ivanhoe Broadcast News in 2022.
Lots of concern about melanoma and certainly vitiligo, the skin pigmentation condition. Can you talk to me a little bit about what you and your colleagues in this lab have determined and what you’ve been studying?
ABDEL-MALEK: So it all started with interest in understanding how normal human pigmentation is regulated. So we made- we were about the first, among the first to discover that in humans skin, the pigment cells, which are called melanocytes, express a receptor that’s called the melanocortin-1 receptor. So the name suggests that it binds to melanocortins. And the main one of which is Alpha MSH melanocyte-stimulating hormone. And as the name indicates, it binds- it activates the melanocytes to make pigmentation. So MSH is preserved in many mammalian species and there has been tremendous amount of work that has been done, particularly using mouse coat color to understand the role of the MSH and regulating dark or light color. However, when we started the research on Alpha MSH, it wasn’t really known if it has any relevance to human pigmentation. So we were the first to show that indeed human melanocytes that we cultured from human skin on regular basis do respond when we treat them with MSH, with increased pigmentation. And then we demonstrated that this is mediated by activating a receptor called the melanocortin-1 receptor expressed on the cell surface of the melanocytes. So this was the very first publication- major publication from the lab demonstrating the role of this MC1R Alpha MSH system in regulating pigmentation in humans. Then came studies not from our lab, but from various epidemiologists and population geneticists worldwide, starting from Australia and Northern Europe, demonstrating that the gene for MC1R can have so many different variants or alleles. The most active form or allele of the receptor is expressed mainly in African nations, predominantly. And this makes a lot of sense because this active receptor is important for making pigment to protect people living in equatorial areas with a lot of exposure to the sun. However, there were a few, less than five allelic variants that were shown to be strongly associated with red hair, light skin color, and inability to turn when exposed to the sun. And those then were shown to be associated with increased risk for melanoma. So this really triggered our interest in understanding the role of MC1R as a melanoma susceptibility gene.
When you have it pinpointed down to the genes, what can you do from there? What did you do? What did you and your team do from there?
ABDEL-MALEK: Well, what we did, we really wanted to have- to develop the basic understanding of how these particular variants impact how the melanocytes respond to MSH or how the receptor is active or not. So we collaborated with an amazing dermatologist, MD PhD, who provided skin samples from her patients that come for regular visits because they know they have a high risk. They don’t necessarily have melanoma but have high risk because of the red hair. So we took the skin biopsy, grew the cells, sequenced the gene, demonstrated the expression of these analogs, and then looked at what happens when you stimulate these cells with MSH. And what we showed is that they have a reduced response. So it really depends. If you are what we call heterozygous, meaning you have only one of these alleles, you have a little bit reduction in your MC1R activity. However, if you have two of those alleles, then you have a double whammy and you’re probably not going to respond to MSH or to anything similar to MSH. And you’ll need to use something downstream from the receptor to activate pigment formation. But this explains why those people do not turn when they go out in the sun. And they have the high risk because they don’t have enough DNA repair capability and they do not have the protective pigments. So this was a milestone paper. It’s got a lot of publicity because it really demonstrated the- how MC1R is important for prevention of skin cancers, particularly melanoma.
Now that you know that this is important for prevention, what do you do with that information?
ABDEL-MALEK: So what we do is we know that melanoma is people that are heterozygous, meaning that they have one of these bad alleles. I’ve got to call them, or loss of function alleles. They have a reduced activity of the receptor, which we can increase by having exogenous application of something similar to MSH that activates the receptor. And also there are other mutations in other genes that are known to increase susceptibility to melanoma, such as the p16 gene, which is coded by the CDKN2A locus. So familiar with melanoma patients that have mutations in p16 and having very high risk for melanoma. They can benefit- if they have an active MC1R, they can benefit from activation of this receptor to delay and prevent melanoma formation.
Can you speak a little bit about how the science is going from here in your lab to the next step, which may down the road be a commercial use?
ABDEL-MALEK: What we have done is knowing the important roles of MC1R activation, not only for melanin formation, but prevention of DNA damage, repair of damage from the sun, and prevention of melanocytes death, which is of course, represents many pleiotropic effects that could be applicable not only to melanoma or to the cosmetic tanning, but also to treatment of vitiligo and a hyperopic mental disorder. So what we have done is I teamed with a group of medicinal chemists here at the University of Cincinnati in the College of Pharmacy and also a good friend and colleague at the University of Minnesota. So we developed small peptide analogs of MSH. And I need to preface that the idea of developing analogs of MSH is not unique to us. Actually, I graduated from the University of Arizona and my mentor was really the very first person to make potent analogs of MSH, which we had done- the unique thing that we had done is we narrowed down the structure of those peptides from a full length 13 amino acids, physiological MSH, to only three or four amino acids based on the structure of MSH. So our peptides are totally unprecedented in their small size. Another very important thing is that those peptides prove to be very highly selective for the receptor, which means you’re not going to have off-target or side effects by binding non-specifically to other receptors expressed on the melanocytes or even other cell types in the skin. And the third thing, first, the small size and the potency of the tetrapeptide. Our tetrapeptides for amino acids are 10-fold more potent than MSH. So you would need much less quantity to activate the receptor. So these all together led us to team with our wonderful consultants and collaborators at the Venture Lab here at UC. So we have three patents that have been issued internationally. And they also helped us with providing funding to move on with the work through the pre-accelerator program, and then getting grants- additional grants through them and through the state of Ohio through the Third Frontier program. So recently we’ve got the Phase 2 grant approved from the Third Frontier for one year. And we had to establish a company, and this is also the startup company was with the help of the consultants in the IP office at the UC Venture lab. So we have a small company called MC1R Ventures. And this is to conduct pre-clinical studies with our peptides teaming with outside industries that are qualified for example, or have the experts in putting out peptides in a topical formulation. This, you can imagine it’s so much easy to just have something that you can apply on your skin. In the case of vitiligo treatment for example, I can envision that the patients would only use it under deep pigmented skin areas, not on the entire skin. But if you want- if you anticipate, for example you want to go on vacation to the beach, you apply this on your entire skin few days before you go on vacation to get the benefit of getting a little bit tan and to activate the DNA repair mechanisms so when you go out in the sun, you’re not going to have the drastic and dangerous effects of sun exposure. But importantly also, is the cosmetic part which is de-tanning. You know, there’s- there’s a huge market for tanning agents and we know that there are some sprays that have been developed commercially. But again, those are not always the best because I haven’t- I don’t have personal experience with them, but like they cause streaking, they’re not permanent, and honestly the tan that they produce doesn’t look anything like a natural tan. Here what you’re doing with our peptides is you’re activating your skin’s natural ability to increase pigmentation but without the disadvantage of being exposed to the sun.
How far away are you from this being a commercially available product in your mind?
ABDEL-MALEK: In my mind, if everything goes well with teaming now with two different companies that are helping us with the topical formulation. If we went on that part and we have an effective topical formulation that we need to start with the animal studies that would eventually lead us to the human- to the Phase 1 human trials. So it’s all dependent on crossing this bottleneck of the topical formulation. If we get that, I can anticipate that maybe within one year we can get the cosmetic aspect approved. Within 2-3 years we can have the clinical applications particularly for vitiligo. This is what the NIH has been- the skin institute at NIH had encouraged us to go that path because there is a very big unmet need for treatment of this disease.
What kind of medical need does this mean?
ABDEL-MALEK: Well, vitiligo is the most common hypopigmentation disorder in humans with about 0.5-2 percent of the world population having this disease regardless of your skin type or ethnicity. In some parts of the world, because of environmental exposure and genetic reasons, it can be as high as eight percent of the population. It’s a very difficult disease to treat. It begins in the early childhood, it’s an acquired disease. So you can imagine a child 10 years of age having this problem and the misunderstanding and the bullying and then the impact on the psychological impact of the disease on particularly children and young adults and women. So there are some treatments but it takes a very long time. In many cases it may not be very effective. It’s unpredictable. And now there is a trend and it’s known that you need to have a combination of therapies. And there has been previous studies showing that treatment with an run along of MSH could enhance pigmentation in combination with narrow bands UVB that’s typically used for the treatment of vitiligo. So we have high hopes that our peptides could be very efficacious in the treatment in restoring pigmentation in vitiligo. On the melanoma side, we know that unfortunately the incidence of melanoma has only been increasing for decades now and prevention obviously is very important because again, treatment of melanoma is not always very effective despite the successes in immunotherapies and targeted therapies. Still the toxicity, the cost, the comorbidities, and so on. So obviously, there is a big need for developing prevention strategies and MC1R could be one of these lines to pursue.
Is there anything I didn’t ask you that you would want to make sure that people know about what you and your team are doing here?
ABDEL-MALEK: Well, I just want the public to know that investments in basic research is so important. I think the most important thing for us, and I appreciate the opportunity to speak here because we do not live in silos and we shouldn’t be. We really need to bring our discoveries out to the public eye and to show that what we are doing really makes a difference in people’s lives and this is something that is really worth investing in and taxpayers money is not going yellow in a hole and not having an impact on human health. I also want to say that there’s a wonderful- I don’t know if you can include that, a wonderful foundation in town here called the Melanoma No More, that has been really super supportive for us. So again, philanthropy, investing in science is really very crucial. There’s been some immediate needs for us in the lab that I did not have immediate money available to support and they came through and helped us acquire. And I can show you some of these equipment that they bought for us the other day. So that’s has been really very helpful.
END OF INTERVIEW
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