Pamela Cassidy, Ph.D., is a research associate professor in the Department of Dermatology at OHSU. Her research focus is on melanoma chemoprevention – developing agents that ameliorate the pathophysiological processes resulting from ultraviolet (UV) radiation.
Where were you before coming to OHSU?
I was at the University of Utah. I did my graduate and postdoc work there and then spent the last 15 years at the University of Utah’s Huntsman Cancer Institute. So, in total, I was at Utah for 25 years!
What brought you to OHSU?
Sancy Leachman, M.D., Ph.D., and I worked together in Utah and she moved here to become the Chair of Dermatology. She ended up offering me a job, so I came for the opportunity to continue to work with Sancy and for the growth opportunity and resources OHSU presented.
How did you get involved in dermatology?
I’ve always been interested in antioxidants for prevention of cancer. The melanoma researchers in the Department of Dermatology at Utah were kind enough to share their expertise in animal models with me, so because of that relationship, I sort of fell into looking at melanoma as research focus.
I’m actually a chemist by training, so the biology of skin pigmentation is really fun for a chemist to think about. Looking at the chemical details of how pigment gets made and how UV light affects the skin is absolutely fascinating to me. As a basic scientist, I think about it in different ways than others might. Dermatology also presents wonderful clinical and translational opportunities to study cancer prevention and treatment because the tissue we’re interested is right there on the surface, making our work relatively non-invasive. We learn a lot about the basic science from our mouse models, , but we need to be able to figure out how to do the same research within humans. Dermatology provides opportunities to do this.
What are some of the factors that contribute to melanoma?
UV-induced oxidative stress is a key driver of melanoma formation. Pigment-producing cells, known as melanocytes, transfer packets of pigment to keratinocytes, which then use them to cover the nucleus of the cell like an umbrella, protecting the DNA. But we know that pigment can also cause problems. For example, redheads are more susceptible to melanoma due to mutations in the melanocortin-1 receptor gene (MC1R). Even people with a redhead in their family, but who don’t have red hair themselves, have at least a two-fold elevated risk for melanoma. Red pigment (pheomelanin) is less protective than darker pigment (eumelanin), and there’s even some evidence that suggests it’s is pro-oxidative. Pheomelanin is a polymer of the amino-acid cysteine (as well as tyrosine). So we’re trying to establish ourselves as experts on how pigment-producing cells use cysteine to support the cells’ natural antioxidant processes and how polymorphisms (in MC1R, the “red hair gene”) affect the way the cell uses cysteine.
What specific avenues of research are you exploring?
I study antioxidants as chemoprevention for melanoma by looking at various agents to see if they can alleviate the mutagenic effects associated with UV exposure. Antioxidants are all about prevention. But the dirty little secret about antioxidants is there is mounting evidence, including some from clinical trials, that some of cancers get worse when you take antioxidants. In fact, we’ve already come up against one example in our research. The first agent we examined in our pipeline was topical selenium. When we applied selenium before UV exposure in our mouse model, it delayed formation of melanoma. However, if we continued to apply selenium after tumors developed, they grew faster. So we dropped topical selenium as a research focus because of our concerns for safety. Many of our patients are people with family histories of melanoma or who have been over exposed to UV radiation, so we can’t take the risk of using an agent that could make an early stage cancer worse. You have to understand how each antioxidant operates on the molecular level and exactly which stage in the progression of disease you’re treating. The drug may not have the same effect at all stages, so we try to model it and understand exactly how the drug works on each stage of the disease before we take it into a Phase III trial. The good thing is our pipeline includes models that will detect agents that may encourage tumor growth if used at the wrong stage in cancer progression.
Currently, I’m co-PI on a NCI-funded Phase II clinical trial, looking at another antioxidant called N-acetylcysteine. The patient treatment is still back in Utah where I started the study, but the basic science work is being done here at OHSU. Our lab is doing some genome engineering to look at the genetic factors that influence whether or not a person will benefit from the drug. We have preliminary data that tells us that if you’re a redhead, you might not respond to our drug as well, and we’re trying to understand why this is on a molecular level. We chose another agent in our pipeline, sulforaphane, because evidence shows that redheads will respond to it, so we can start looking at the differences in these drugs. I’m anxiously waiting for the Phase II results to be unblinded so I can start looking at the data.
I also work with Sancy [Leachman] to support her efforts to understand familial melanoma in a broader sense. We very much work as a team – she’s my clinical partner. We have a grant from the DoD and a another developmental grant from NIH, to study cells from patients who have both a highly penetrant mutation in the gene that incodes the tumor suppressor p16, and in the MC1R (which causes red hair) . Those studies are ongoing.
Finally, we are working with biomedical engineering to develop non-invasive means of testing our therapeutics. We’re looking at applying topical creams and then using sensors to measure antioxidant activity, as opposed to having to slice off a piece of skin. On the long-term horizon, we want to find non-invasive ways to measure whether or not our drugs are working.
Is melanoma on the rise?
Unfortunately, yes. And Oregon just made it to the top of the list for rate of melanoma in women. We don’t know why. You can find out more about this on the War on Melanoma page, and a link to the melanoma community registry can also be found there. We now have over 3,000 participants in the registry, and from that group, I hope to identify the participants in my Phase III trial. Our melanoma group is writing a big U01 grant right now that will support melanoma research at OHSU with access to patients from this registry.
Because this is such a deadly cancer I’ll put my plug in for wearing hats and sunscreen; and always use the zinc oxide type sunscreens rather than chemical sunscreens. My dad and his twin brother both had melanoma, and I know from using my own DNA to develop methods for sequencing that I’m at increased risk for the disease; I’m pale for a reason.
What do you do for fun?
I’m a fly fisher, and I love going out to Eastern Oregon to enjoy all of the natural beauty there. I also play viola in the Hillsboro Symphony. But honestly, I’ve been very caught up in my work since we moved here, and that’s how I spend most of my time!