Researcher Q&A: Dr. John D’Orazio

In the latest blog post, we chatted with the University of Kentucky’s John D’Orazio, M.D., Ph.D., a pediatric hematologist oncologist, and a 2015 MRA grant awardee. Read on to learn what he has to say about melanoma research and prevention efforts.

How did you get interested in melanoma and your field of research?

I am a physician scientist who combines a clinical career in pediatric oncology with basic research aimed at understanding the molecular mechanisms of melanoma development. Kids don’t usually get melanoma, thankfully. But prevention is such an important part of combating this disease – particularly during childhood since pediatric UV exposure plays such an important causative role for melanoma later in life. My overarching interest, related to pediatric oncology, is understanding cancer predispositions.

Tell me about your research.

During my fellowship, I paired up with Dr. David Fisher, who is one of top melanoma biologists in the world and who happened to also be my ward attending on the pediatric oncology service at Boston Children’s Hospital. David approached me with a research project relating to understanding why fair-skinned people get melanoma so much more than dark-skinned individuals. We knew it wasn’t just about melanin since albinos – people with normal numbers of melanocytes but who don’t make melanin at all because of inherited defects in melanin synthetic enzymes – almost never get melanoma.

In the Fisher lab, I focused on the contribution of the melanocortin 1 receptor (MC1R) in pigmentation and melanocyte UV sensitivity. We chose to study MC1R since loss-of-function MC1R polymorphisms are very common among fair-skinned people and raise lifetime melanoma risk by about four-fold. Using a unique mouse model that I developed, David and I discovered that MC1R controlled whether a mouse’s skin would express dark or light melanin.

We found that pharmacologic replacement of MC1R signaling function, through the topical application of cAMP-promoting drugs to the mice, was enough to turn the skin from a blonde UV-sensitive and cancer-prone complexion to a heavily melanized UV- and cancer-resistant phenotype instead. We had demonstrated sunless tanning by pharmacologic manipulation of the MC1R signaling axis, suggesting that skin could be shielded from UV damage by melanin stimulation.

Since establishing my own lab, we’ve focused on other ways in which MC1R signaling enables melanocytes to resist UV damage and carcinogenesis. We’ve been studying how cAMP signaling increases the efficiency by which melanocytes recover and repair UV DNA damage.

How has MRA funding helped your work?

MRA funding absolutely lets us open up a new avenue of research that wouldn’t have otherwise been possible. We’re still focused on MC1R signaling but are now funded to study the natural hormonal regulation of this pathway in the skin. The MRA grant allows us to study how the pathway impacts melanoma risk on multiple fronts.

What do you hope to see more of in the future of melanoma research?

Melanoma incidence just keeps getting higher. Whatever is underlying it, we have to do something about it. Almost 2% of the population is going to be affected by melanoma in their lifetime. It’s a big problem, and although exciting advances are being made in the field of anti-melanoma therapeutics (especially targeted therapy and immunotherapy), it is still far better to avoid the disease in the first place. I would like to see more focus put into active melanoma prevention, not only through policy and indoor tanning regulation, sun protection, and public health aspects, but by using a science-based approach to enhance the skin’s ability to resist UV-mediated carcinogenesis.

What do you do when you’re not seeing patients or conducting research?

I’m a family guy. I have one daughter, a wife who is in science, and a dog. I love to cook, enjoy nature photography and have gotten pretty good at pickleball.

 

Learn more about MRA’s Research.

 

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