Sancy Leachman, MD, PhD, is director of the Melanoma and Skin Cancer Program at Knight Cancer Institute; professor and chairwoman of the department of dermatology at Oregon Health & Science University; co-chair of the Southwest Oncology Cooperative’s Melanoma Prevention Working Group; and principal investigator of the WarOnMelanomaTM. She met with The Dermatologist to discuss skin cancer—particularly focusing on melanoma—and other related cutaneous cancers.
Based on recently published research,1 can you explain the potential mechanisms of statins on melanoma metastasis, and how may this impact skin cancer treatments going forward?
Statins have been previously studied as preventive agents for melanoma—this is not the first paper by any stretch of the imagination. There have been several epidemiological studies looking at statins with all kinds of cancer including melanoma. These studies were mixed; some showed potential prevention benefit and others did not. The backstory is that years ago, when pharmaceutical companies tested statins as cholesterol lowering agents, they were required by the FDA to track cancers to prove they were safe. They found that they were safe with respect to cancer, basically no cancer increase, but surprisingly, melanoma rates actually appeared to go down in statin users in some of the trials. That was one of the first indications that maybe statins were preventing melanoma.
Because statins are relatively safe drugs, many scientists began to wonder, could you use a statin as a prevention agent? So, a group of us, led by Frank Meyskens and Ken Linden, did a clinical trial2 to investigate what happens to atypical moles (possible precursors to melanoma) in people when they take a statin. The idea was, if statins have the potential to reduce the chance that a mole will change into a melanoma, we might be able to observe changes in the appearance of atypical moles—making them more “normal” and less atypical looking by eye or under the microscope. In other words, could we tell whether giving people statins had a positive effect on these bad moles?
In the end, we found nothing in that study. They did not seem to change at all. We could not prove anything. However, just because we did not see a change in moles does not mean that statins do not have the ability to prevent melanoma, it just suggested that the mechanism by which it was preventing it was not by converting atypical moles to normal-appearing moles. It also does not prove that the studies that seemed to show a beneficial effect of statins were wrong–just that the mechanism was likely something else. So what could it be?
The more recent paper1 sheds some important light on this subject! Our work was led by Dr Wesley Yu, an up-and-coming physician scientist in our group. In his study, when he treated melanoma cells with a statin, the cells reacted by changing their expression of a lot of different proteins. When he looked at the pattern of expression changes that the statins caused, he noticed a very interesting pattern. Basically, the pathways that the statins activated were pathways previously known to be involved in cancer metastasis. This finding suggested that the mechanism by which statins might prevent melanoma was not by preventing melanoma development, but rather by preventing a melanoma from being able to spread. In reviewing the literature, he also found supporting evidence that statins might affect melanoma metastasis through decreasing cellular motility.
With this data in hand, we then wanted to see if there was any evidence of an antimetastasis effect of statins in patients—to see if it was promising in humans. Our work was the first to demonstrate this association in patients with melanoma—suggesting a molecular mechanism for the effect. Dr Yu and I have recently completed some additional studies that we will be publishing soon that corroborate our findings and further demonstrate a potential new mechanism for the statin effect.
These results are really promising, because if we could use statins in people that have had a melanoma and reduce the chances that they are going to develop a metastasis, it would be a major step forward. It would be a major advance with low toxicity, and it is a proactive approach to patients who have developed a melanoma.
In that study,1 patients with melanomas who were concurrently treated with statins had thicker primary melanomas with a higher mitotic count, despite those patients having fewer metastases even with presumed later diagnosis and progression. Why do you think this was?
We were surprised by this result as well! The fact that patients with more locally advanced melanoma were less likely to have metastasis when on a statin really seems to indicate that statins have a strong effect on the metastatic process. The clinical findings support this hypothesis because if it was a preventive, those patients who were on statins would have had thinner tumors. That is what we thought we were going to see. However, they did not have thinner tumors, because statins apparently are not preventing the tumors from developing; they are preventing them from metastasizing. It is acting in a different way than people have considered before. This data shows a strong association between taking statins and decreased metastasis, and we are now following up with several studies to prove a causative link.
Any pearls of wisdom you would like to share with your colleagues regarding skin cancers?
There is a melanoma early detection campaign called the War On Melanoma (www.WarOnMelanoma.org) that we are doing where we have about 11,000 patients in a research registry who are participating in various studies. We now have participants in all 50 states, and we would love to have more participation.
The second website that I would encourage everyone to look at is called Start Seeing Melanoma, which is nonbranded (www.StartSeeingMelanoma.com). This site is directed toward capturing the attention of lay people that “don’t care,” that is, they are not worried about getting melanoma at all and do not want to think about it. The website is trying to increase awareness in people that have no belief that it even applies to them. We have a very cool risk calculator online on this site that is fun to take and gives people the opportunity to assess their own level of risk and what they might want to do about it if it is high.
Additionally, there is an app called MoleMapper. MoleMapper is a mole tracking app on iPhone and it is also a research app that iss free. It cannot determine if you need to do a biopsy or make a diagnosis, but can help an individual track their concerning moles more carefully.
Read more of our interview with Dr Leachman by clicking here!
References
1. Yu WY, Hill ST, Chan ER, et al. Computational drug repositioning identifies statins as modifiers of prognostic genetic expression signatures and metastatic behavior in melanoma. J Invest Dermatol. Published online January 6, 2021. doi:10.1016/j.jid.2020.12.015
2. Linden KG, Leachman SA, Zager JS, et al. A randomized, double-blind, placebo-controlled phase II clinical trial of lovastatin for various endpoints of melanoma pathobiology. Cancer Prev Res (Phila). 2014;7(5):496-504. doi:10.1158/1940-6207.CAPR-13-0189
