Outshining the sun to squash skin cancer

Residents of the sunniest state – Arizona – are no strangers to ample sunshine. While sun exposure is beneficial to our wellbeing, it’s also a major cause of skin cancer, the most common type of cancer in the U.S. At least 5 million people in our country are treated for skin cancer annually, resulting in more than $8 billion in medical expenses. Physician-scientist Dr. Clara Curiel is a professor of medicine and Director of the Multidisciplinary Cutaneous Oncology Program at the UArizona Skin Cancer Institute. Dr. Curiel-Lewandrowski is also the interim chief of the Division of Dermatology, member of both the BIO5 Institute and UArizona Cancer Center, and Program Director for the Dermatology Residency Program. Her research and innovative approaches to solution-based translational science addresses important clinical gaps in skin cancer prevention and early detection.

Tell us a bit about your background and how it has shaped your career aspirations.  

I have always been fascinated with science and especially with medicine. I come from a family of physicians, and I did see my grandfather succumb to metastatic melanoma, despite being a physician of metastatic melanoma. It is something we understand very well from what is happening, but the challenge is if we stop it from happening.

We know that 99% of skin cancers are due to sun exposure - this association is equal or even stronger than tobacco and lung cancer. It’s a carcinogen, so what's going on here? Why are so many people still dying? We have a disease that is almost 100% preventable, and that's where we've come into place as scientist-physicians to move the needle and make a difference on something that should have a solution.

I finished medical school and went straight into the research – I love science - and I decided to do dermatology and skin cancer work. When we think about skin cancer, you ask yourself, “Where are the opportunities to make a difference?” There are different stages of what we call skin carcinogenesis - from the beginning to the end of it.

One is prevention, and primary prevention means that we're capable of stopping cancer from happening all together. Secondary prevention is also known as early detection, so if we can't stop it from coming, we try to find it early so we can maximize the outcome of intervention.

Then you have therapeutics - you couldn't diagnose it early, and it's more advanced, so then you develop treatment options that are more effective.

Here at the Arizona Cancer Center and the Skin Cancer Institute, we are working every single aspect of this journey to be able to have an impact and decrease the number of skin cancers and people dying from them.

Can you talk a bit more about prevention and how your team makes a difference in that area?

When it comes to primary prevention, there are different strategies. One of them is typically known as a behavior modification which is about protection or avoidance – using sunscreen, wearing protective clothing, avoiding a big exposure of sunshine. 

We do know these can be difficult to achieve because as humans, we enjoy being out there and as much as we want to live in harmony with the sun, sometimes it's not possible and people get their sunburns and long-term exposure. So, this is one aspect of primary prevention that will continue to be enforced, but we try to do education early on. It’s proven that the earlier you can intervene with this kind of education, the more effective you can be.

However, there is another type of prevention that we also work quite extensively on known as therapeutic prevention. Therapeutic prevention means that if you couldn't completely avoid some of the damage, can you reverse that damage or prevent it from continuing to happen. There are ways that we can identify in sun-damaged skin someone that has been exposed to the sun for an extended period of time and is in the process of developing a skin cancer, a very specific cellular mechanism - our signatures - that the cancer might occur. We might be able to target it effectively by developing new drugs that can reverse or prevent that process.

This is where we have a fascinating and very exciting grant here at the Arizona Cancer Center where we have identified two targets within the skin cells – one is an immune mediated molecule, and the other is related to cell proliferation (multiplication) and differentiation (specialization).

Now by the identification of these two targets, we have work over the past three years on pushing forward new formulations of a drug that we know that can inhibit them. By doing thiis, we are able to apply this to someone’s skin at risk and are able to prevent particularly squamous cell carcinoma.

There are multiple types of skin cancer, and combined, they make skin cancer the most prevalent type of cancer. There are two main types of skin cancers, known as non-melanoma skin cancer and melanoma skin cancer. Melanomas are probably the one that everyone is familiar with because they have the highest mortality rate, but they also only account for about 3-4% of all cancers. The other 95% of skin cancers are driven by what we call non-melanoma skin cancer, mainly known as basal cell carcinoma (75%) and squamous cell carcinoma (25%).

Basal cell carcinomas rarely metastasize, whereas squamous cell carcinomas have a higher rate of metastasis. Our approach for therapeutic prevention - slowing down the progression of carcinogenesis - is mainly targeting squamous cell carcinoma. The reason why we have focused on this particular subtype is because they have a precancerous lesion known as actinic keratosis (AK), and probably most Arizonans eventually will become familiar with that term.

They have a rate of transformation of approximately 1% per year, but when you have AK, typically people don't have just one, so when you start adding the risk, it can become significant. This is why having the opportunity to have a precancerous lesion that happens to develop to cancer over time allows us to have different samples at different stages of carcinogenesis. That allows us to study the journey of a normal cell to sun-damaged cell to AK to squamous cell carcinoma.

When you compare either the proteomics - the protein produced by these cells - or the genes expressed in a sequence or progression within the same individual, it really is a powerful opportunity to identify targets and develop solutions.

How do biology, the environment, and genetics work together in your work?

There inevitably is a genetic and familial component to skin cancer, but what I do try to tell our patients is that you really can win this battle. We can win the battle because we have better treatments - today, we can intervene earlier. We have different modalities that didn't exist before. If you are consistent, you can go to a dermatologist and tell them, “I want to be ahead of the game, so how can I reverse this process?”

It is totally doable, but it does require that mindset of that you’re going to take care of this and be ahead. Some of these treatments are not easy for prevention - they can cause a lot of inflammation, they are irritating, and they can have other systemic side effects that no one wants to experience, but for the most part, they're not life threatening. It just requires time, dedication, and having that relationship with your dermatologist and your other providers to be able to tackle it early on.

What types of sunscreens and sun-related clothing would you suggest?

Starting with sunscreen, there’s sunscreen and sunblock. Sunscreens contain chemicals that are able to quench the effect of UV radiation into your skin - any of those radical oxygens and so forth are generated from UV exposure in your skin, and sunscreens basically absorb that. Sunblock is a physical blocker that creates a layer on top of your skin that prevents sun from penetrating your skin altogether. 

The two most typical types are titanium dioxide and zinc oxide. It used to be that no one wanted to use them because they're thick, but now they are micronized and they're very easy to apply with different formulations. If you really want to be thorough and protect as much as possible, go after your physical blocks.

Of course, clothing - we always say that's the easiest. There used to be this ugly looking type of SPF clothing, but now it’s even fashionable. It really enhances the adoption of this approach, which is a must in Arizona. Whatever is not protected with your clothing, put your sunblock on, and you should be good. Remember to reapply – sunblockers and sunscreens do not last all day, so every two to three hours, it is a good idea to put it back on. 

All of these approaches keep you living in harmony with the sun. 

If you can't stop the process, and you get to the point where you are ruling out skin cancer, this is where the technology has also moved forward. Now we have fascinating tools for early diagnosis, and I think it's important for the patients to know about these and the public to know about these.

Typically, when you have a suspicious lesion the first step is to do a skin biopsy because our gold standard is to look at the skin on the microscope, but the good news is now the microscope can also look at your skin without doing a biopsy. For the past almost 20 years, there has been a technique called in vivo confocal microscopy - life microscopy -  where you're able to put a microscope on top of your skin and be able to visualize those cells without you going through a surgical procedure.

We're very lucky that we recruited here at BIO5 and the College of Optical Sciences, Dr. Dongkyun Kang about six years ago whose work is really to make in vivo confocal microscopy accessible to a larger group of individuals. One of the challenges with this life microscope is that it is bulky, expensive, and not easy to be adopted for these reasons into clinical practice, but what Dr. Kang has been able to do is miniaturize this equipment to the size of a laptop on a handheld piece which you can easily place it on the screen and visualize any kind of skin lesion up to about 300 microns, which is a reasonable depth to see most type of skin cancers.

So, for the past five or six years, we have been working together, and this is one of those wonderful opportunities working at university where team science really happens. In this example, we have biomedical engineers working with clinicians really trying to fill this particular gap in our care, and we are currently using the instrument trying to move that needle forward and trying to commercialize it more effectively so more and more dermatology practices across the country can implement this technology.

How does your investment in the training of medical residents, as well as KEYS students, benefit affect you, and how meaningful is that to you?

I think the best way to put it is, “What is the meaning of anything you're doing if it's not passed on to someone who can do it better than you do?” That's a real concept of evolving and transforming because it's not static - for me as a physician-scientist, there is only so much I can accomplish myself, but the real success is when you have a team of people that share a vision. They understand the needs and the gaps, they want to be part of the process, and they all contribute in their own way with their strengths. 

I like to focus on people's strengths, not necessarily their weaknesses. If we spend the time correcting people's weaknesses, we will never get forward, but the strengths are what fascinates me the most. They're so easy to identify when you work with them, and that is a real driver.

I think just being in a university where we're surrounded by opportunities - you have the patients in front of you with a problem and need, and then you reflect. Sometimes it works perfect and there's no need to do anything else but in so many instances, there is something we could be doing better, so the opportunity to train somebody to get very quickly up to speed onto what is available now and the way of thinking and decision making, but also plant that seed of curiosity and support them and close the gap with their own team is part of the process. It eventually becomes second nature like we're not thinking about it anymore - it's just the way we function, how we operate, and I think that's probably part of the magic in all this.

Regarding mentoring KEYS students, I have mentored kids since high school that knew exactly what they wanted to do, which is really interesting, and there are those that do not, but I think you have to expose them, you have to give them the opportunity to see what is available out there. Then just be part of the process of finding their way. It’s important they find what really matters to them - it's priceless.

You were part of our BIO5 Inspiring Women in STEM panel last year. As a woman in STEM, do you have any words of wisdom for a young girl looking to pursue a career in science or medicine?

I really find that girls these day barely find a barrier for them to really achieve what they want to achieve in life, which is wonderful to see, but we're in a very unique position in this country to do that – it doesn't happen everywhere. Hopefully we'll get there one day.

Irrespective of anything, clarity and resilience are very important. If you are clear and understand your path, stick with it. If that's what you want to achieve but if you don't find the right support here, keep seeking it because it's out there. You haven't had the opportunity to find it yet, but don't give up. The resilient aspect is important. 

It doesn’t matter how long it takes you. It just means that there is something along the way that you’re supposed to learn. It’s not wasted time. It took me a lot longer than other people to get into dermatology here, which is very competitive in the US, but I had to do more research. For me, it wasn’t a penalty, it was something I’m very grateful I did because most of my immunology background comes from those years. The fascinating part is that now I probably know more about it, so I can relate more in a team science group than if I didn't have that toll that I needed to pay 20 years ago.

Don't necessarily question the hardship - embrace the hardship - because it is part of the process and it’s going to get you ahead eventually. You just don't know yet what it's going to mean to you, so stick with it. Be resilient. Be clear. Keep going after that goal, and you will get there.

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