Skin cancer on the rise

New diagnoses for two types of skin cancer increased in recent years, according to a Mayo Clinic-led team of researchers.

Their paper, published today in Mayo Clinic Proceedings, uses medical records from the Rochester Epidemiology Project to compare diagnoses of basal cell carcinoma and squamous cell carcinoma — both nonmelanoma skin cancers — between 2000 and 2010 to diagnoses in prior years. The Rochester Epidemiology project is a medical records linkage system and research collaborative in Minnesota and Wisconsin.

Age, sex lead to different diagnoses

The researchers report that, between 2000 and 2010, squamous cell carcinoma (also called cutaneous squamous cell carcinoma) diagnoses increased 263 percent, and basal cell carcinomas increased 145 percent. They compared the 2000-2010 period to two other segments of time: 1976-1984 and 1985-1992.

Women 30-49 experienced the greatest increase in basal cell carcinoma diagnoses; whereas, women 40-59 and 70-79 experienced the greatest increase in squamous cell carcinomas.

Men had an increase in squamous cell carcinomas between the first and second time period studied (1976-1984 and 1985-1992), but experienced a slight decline in the 2000-2010 period. However, for basal cell carcinomas, men over 29 showed similar increases in diagnoses in the 2000-2010 period then the two earlier periods.

Tanning: Beautifying or death-defying?

“We know that the sun and some artificial sunlight sources give off skin-damaging ultraviolet, or UV, rays,” says Christian Baum, M.D., a Mayo Clinic dermatologist and the study’s senior author. “This skin damage accumulates over time and can often lead to skin cancer.”

“Despite the fact that sunscreens and cautionary information have been widely available for more than 50 years, we saw the emergence of tanning beds in the 1980s, and tanning – indoors or out – was a common activity for many years.”

Although Dr. Baum notes that tanning has slowed, tanning beds still exist, and beaches will never be empty. But what people should remember is that the damage accumulates, he says, and “eventually those blistering sunburns of your youth and hot, reddened skin, and peeling shoulders of your adulthood can add up to one or more skin cancers.”

The authors also reported that shifts in exposure to UV light may be the reason for a location shift in where the cancer tumors are found. In the earlier time periods, both basal cell and squamous cell carcinomas were diagnosed more often on the head and neck. But, in the most recent time period, the records showed that basal cell tumors on the torso increased, as did squamous cell carcinomas on the arms and legs.

Dr. Baum says that the risk of cancer should provide the ultimate argument for using sunscreen – every day, year-round on all exposed skin.

“Use sunscreen,” says Dr. Baum. “This includes on your left arm for those who do a lot of driving. UV rays can penetrate car windows and exposed skin — even when the sun isn’t shining. UV rays bounce around under the clouds, off the snow, buildings, and more, causing damage — even on gray days.

More on the data

Using the Rochester Epidemiology Project medical records linkage system, the research team was able to identify nearly all of the Olmsted County, Minnesota, adult residents who received an initial diagnosis of the most common nonmelanoma skin cancers — basal or squamous cell carcinoma (or both), during the 2000-2010 period and the comparison years.

“There is no tumor registry for these types of cancer,” says Dr. Baum, “So it is difficult to have accurate estimates of the national or worldwide impact of these cancers. However, because the Rochester Epidemiology Project contains health care information for virtually all residents of Olmsted County since 1966, it provides a good proxy for information on many global population health concerns.”

Beta Blocker Shows Cancer-Fighting Properties

The beta blocker carvedilol could one day be used in creams or sprays that prevent skin cancer

A new study finds that carvedilol, a drug typically used to treat high blood pressure, can protect against the sun-induced cell damage that leads to skin cancer. Researchers serendipitously discovered the beta blocker’s cancer-fighting properties after making an error in the lab.

Sherry Liang, a graduate student at the Western University of Health Sciences College of Pharmacy, will present the new findings at the American Society for Pharmacology and Experimental Therapeutics annual meeting during the Experimental Biology 2017 meeting, to be held April 22-26 in Chicago.

“What began as an experimental error led to a very interesting scientific discovery,” said Ying Huang, PhD, coleader of the research team with Bradley T. Andresen, PhD. “Our research could lead to the development of a class of new cancer-preventive agents.”

Carvedilol’s cancer-fighting properties were discovered when a former graduate student in Huang’s lab was studying whether carvedilol and similar beta blockers might increase cancer risk. The student inadvertently tested carvedilol’s anticancer effect rather than its ability to promote cancer, finding that carvedilol surprisingly showed some protective effects against skin cancer.

The researchers then conducted experiments with cell cultures and mice to see if carvedilol could prevent skin cancer caused by ultraviolet-B (UVB), the portion of sunlight that tends to damage the skin’s top epidermal layers and plays a key role in skin cancer development.

The researchers found that carvedilol exhibited a protective effect in cultured mouse skin cells exposed to UVB and in hairless mice given the drug after UVB exposure. The experiments showed that carvedilol acted by protecting cells against the cancer-causing DNA damage and cell death produced by UVB. Hairless mice exposed to UVB and given carvedilol showed decreases in both the severity and number of tumors that developed compared to those not given carvedilol. The mouse studies also showed that carvedilol delayed skin tumor formation more than sunscreen.

The researchers also discovered that not all beta blockers show cancer preventive properties, indicating that the cancer-fighting beta blockers likely act on not yet identified molecules. “We have preliminary data indicating that the cellular targets for carvedilol are not related to the beta-adrenergic receptors that are the commonly accepted targets for all beta blockers,” said Andresen. “They likely target unexpected mechanisms involved in cancer development.”

The researchers aim to incorporate carvedilol or similar beta blockers into a skin cream or spray that could hopefully be used to prevent skin cancer arising from UV light exposure. The treatment would act on the skin without affecting blood pressure and heart rate, which are commonly altered by beta blockers. Understanding carvedilol’s mechanisms of action could also allow scientists to design completely new treatments that target these mechanisms without introducing any cardiovascular effects.

New Driver, Target in Advanced Mucosal Melanoma

Not all melanomas are created equal. While most melanomas appear on the skin as the result of sun exposure, a small subset of melanomas arise spontaneously from mucosal tissues. And while targeted treatments and immunotherapies have dramatically improved the prognosis for many patients with sun-associated melanomas, these treatments are ineffective in the mucosal form of the disease. A University of Colorado Cancer Center study published today in the journal Melanoma Research uses the unique resource of over 600 melanoma samples collected at the university to demonstrate, for the first time, novel mutations involved in mucosal melanoma, paving the way for therapies to treat this overlooked subtype.

“The treatment for melanoma has gotten pretty good in the past five years. But this is a different disease and the treatments that work in sun-caused melanoma don’t work in non-sun melanoma,” says William A. Robinson, MD, investigator at the CU Cancer Center and the Rella and Monroe Rifkin Endowed Chair of Medical Oncology at the CU School of Medicine. Robinson founded the melanoma tissue bank at CU, which has grown into a major national resource for scientists studying the disease.

The study compared whole-exome sequencing data from 19 patient samples of mucosal melanoma to 135 samples of sun-exposed melanoma. Importantly, mutations in the BRAF gene that are seen in more than half of advanced melanomas were absent in mucosal melanoma, explaining the ineffectiveness of BRAF-targeted treatments like vemurafenib. Instead, 32 percent of mucosal melanomas showed co-mutation of the genes KIT and NF1. Also, the paper reports mutations in the gene SF3B1 present in 37 percent of mucosal melanoma samples.

“We have seen SF3B1 mutation in chronic lymphocytic leukemia and in myeloid dysplastic disorders, and now we show its importance in mucosal melanoma,” says Aik Choon Tan, PhD, investigator at the CU Cancer Center and associate professor of Bioinformatics at the CU School of Medicine.

Because any sample of cancer cells is likely to contain thousands of mutations, advanced analytic tools are needed to distinguish harmless “passenger” mutations from the dangerous mutations driving the disease. For this purpose, the researchers used the computational tool IMPACT, developed in the Tan lab, to sort functional from missense mutations and to cross-reference candidate mutations with those previously reported in other cancer types.

“For the first time, this process demonstrates the functional role of SF3B1 in mucosal melanoma,” Robinson says.

The mechanics of SF3B1 are complex and only partially understood. Basically, the gene makes a molecule involved in preparing other genes for expression, helping to distinguish between regions of genes that should be manufactured and those that are silent genetic filler. Technically, SF3B1 sorts “exons” from “introns” – helping to cut and splice genetic code into the streamlined version that forms the plan for a protein. Unfortunately, if SF3B1 is mutated, this cutting and pasting can go awry in ways that introduce unintended bits of introns along with the intended bits of exons into the blueprint.

“Most often when material from introns is improperly included with exons, the result is nonsense proteins that go on to quickly degrade, meaning that cancer may use this strategy to downregulate the production of certain anti-cancer proteins,” Tan says. “On the other hand, an SF3B1 mutation could result in changes to the protein that are helpful to cancer cells, meaning that mucosal melanoma may be using this strategy to upregulate the production of proteins that can drive its growth.”

No matter if SF3B1 is nixing good proteins or boosting bad ones, the current project shows that stopping its action could benefit patients with mucosal melanoma. In fact, the researchers point out that phase 1 clinical trials are already underway for compounds targeting this gene in other cancers, meaning that the time needed to apply a similar strategy to mucosal melanoma could be dramatically shorter than if they had to start from scratch.

The group plans to continue exploring the mechanics of SF3B1 while also pushing forward with the preclinical work needed to form the rational basis for targeting this gene in patients with advanced mucosal melanoma.

Drug Combination Delivered by Nanoparticles May Help in Melanoma Treatment

The first of a new class of medication that delivers a combination of drugs by nanoparticle may keep melanoma from becoming resistant to treatment, according to Penn State College of Medicine researchers.

CelePlum-777 combines a special ratio of the drugs Celecoxib, an anti-inflammatory, and Plumbagin, a toxin. By combining the drugs, the cells have difficulty overcoming the effect of having more than one active ingredient.

Celecoxib and Plumbagin work together to kill melanoma cells when used in a specific ratio. Researchers used microscopic particles called nanoparticles to deliver the drugs directly to the cancer cells. These particles are several hundred times smaller than the width of a hair and can be loaded with medications.

“Loading multiple drugs into nanoparticles is one innovative approach to deliver multiple cancer drugs to a particular site where they need to act and have them released at that optimal cancer cell killing ratio,” said Raghavendra Gowda, assistant professor of pharmacology, who is the lead author on the study. “Another advantage is that by combining the drugs, lower concentrations of each that are more effective and less toxic can be used.”

Celecoxib and Plumbagin cannot be taken by mouth because the drugs do not enter the body well this way and cannot be used together in the ratio needed because of toxicity.

CelePlum-777 can be injected intravenously without toxicity. Because of its small size, it also accumulates inside the tumors where it then releases the drugs to kill the cancer cells. Researchers report their results in the journals Molecular Cancer Therapeutics and Cancer Letters.

“This drug is the first of a new class, loaded with multiple agents to more effectively kill melanoma cells, that has potential to reduce the possibility of resistance development,” said senior author Gavin Robertson, professor of pharmacology, pathology, dermatology, and surgery; director of the Penn State Melanoma and Skin Cancer Center and member of Penn State Cancer Institute. “There is no drug like it in the clinic today and it is likely that the next breakthrough in melanoma treatment will come from a drug like this one.”

The researchers showed the results of CelePlum-777 on killing cancer cells growing in culture dishes and in tumors growing in mice following intravenous injection. The drug prevented tumor development in mice with no detectable side effects and also prevented proteins from enabling uncontrolled cancer cell growth.

More research is required by the Food and Drug Administration before CelePlum-777 can be tested in humans through clinical trials. Penn State has patented this discovery and licensed it to Cipher Pharmaceuticals, which will perform the next series of FDA-required tests.

Immune Responses Against a Virus-Related Skin Cancer Suggest Ways to Improve Immunotherapy

Researchers at Seattle’s Fred Hutchinson Cancer Research Center and the University of Washington say a new study suggests ways to improve immune therapy for certain cancers including a virus-associated form of Merkel cell carcinoma, a rare, aggressive skin cancer.

Merkel cell carcinoma, or MCC, is 35 times less common than melanoma, but on average, it is about three times more likely to be deadly. There are currently no therapies approved by the Food and Drug Administration for this cancer. About 80 percent of the 2,000 new cases diagnosed in the U.S. each year are caused in part by a virus – Merkel cell polyomavirus – that is often present on normal skin without consequence.

Previous studies have linked a weaker immune system with poorer survival in patients with the disease. In this study, researchers at UW and Fred Hutch, a leading center developing experimental, genetically engineered T-cell therapies, conducted an unprecedented in-depth analysis of the immune system’s “killer” (CD8) T cells that respond to a specific part of the Merkel cell polyomavirus.

The immune system’s effectiveness is determined by many factors, including how well T cells can infiltrate a tumor and bind to the “foreign” proteins, or antigens. More specifically, T cells seek out and attach to antigens using their highly diverse T-cell receptors. In this multicenter study, the researchers focused on T cells that target a piece of the virus referred to as “KLL”.

“We found that a surprisingly low number of patients – only about 20 percent – had T cells specific for the ‘KLL’ region of the virus. This suggests that about 80 percent of patients aren’t making T cells that recognize this very prominent target,” said Dr. Paul Nghiem, affiliate investigator of the Clinical Research Division at Fred Hutch, and professor of medicine, Division of Dermatology at the University of Washington School of Medicine.

Nghiem, senior author of an article published online Jan. 16 in Cancer Immunology Research, said the study is important because an increase in the KLL-specific T cells infiltrating the tumor is associated with a striking improvement in patient survival.

First author Natalie Miller, an MD/PhD student in Nghiem’s research lab, performed in-depth analysis on blood and tumors from 12 patients who had T cells that could recognize KLL.

“T cells that recognize this part of the virus are incredibly diverse. In fact, among these 12 patients, there were 397 unique ways for the T cells to recognize this single short piece of the virus; only one T-cell receptor was shared between two patients,” Miller said. “In addition, T cells from patients with better outcomes tended to stick to the viral target more tightly. This suggests that while nature has created many ways for the immune system to fight this cancer, some ways are better than others. Our hope is that these ‘better’ T-cell receptors can be turned into a therapy for patients who do not have them.”

At diagnosis, virus-associated MCC is typically treated with surgery and radiation, and although 95 percent of patients appear to be cancer-free, the disease returns in about half of cases, Nghiem said. The cancer often responds to chemotherapy, but the response is short-lived, with most tumors progressing about three months after treatment begins.

In April, Nghiem’s group published findings of a phase 2 clinical trial of the immunotherapy drug pembrolizumab, reporting that the “checkpoint inhibitor” helped to revive “exhausted” T cells, providing significant and lasting responses in more than half of patients.

With their new findings, the research team expects to propose the launch of a clinical trial in which T cells engineered with the most effective tumor tracking and attacking receptors would be transferred to patients who are unable to mount an effective immune response of their own.

“Like Merkel cell carcinoma, cancers that have a viral component provide a variety of potential targets for immunotherapy. We’re eager to find out if transgenic T cell therapy can ‘reprogram’ lymphocytes to eliminate tumors in combination with checkpoint inhibition,” Nghiem said.

The study was supported by grants from the National Institutes of Health and other sources including the Adaptive Biotechnologies Young Investigator Award, Kelsey Dickson Team Science Courage Research Team Award, Prostate Cancer Foundation Award, ARCS Fellowship, the David & Rosalind Bloom Endowment for MCC Research, the Michael Piepkorn Endowment Fund, the UW MCC Patient Gift Fund, and the Deutsche Forschungsgemeinschaft (SFB TR36).

Nghiem, corresponding author, is a leading expert on MCC and a pioneer of immunotherapy for the disease. His research has shed light on the importance of the immune response to Merkel cell polyomavirus. A practicing physician, he treats patients with MCC and other skin cancers at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner. He is a consultant for EMD Serono Inc. and receives funding from Bristol-Myers Squibb to perform biomarker studies in MCC clinical trials.

New Topical Immunotherapy Effective Against Early Skin Cancer

A combination of two topical drugs that have been in use for years triggers a robust immune response against precancerous skin lesions, according to a new study. The research, from Washington University School of Medicine in St. Louis and Harvard Medical School, shows that the therapy activates the immune system’s T cells, which then attack the abnormal skin cells.

The study, which involved patients with actinic keratosis, a precursor to a type of skin cancer called squamous cell carcinoma, is published Nov. 21 in The Journal of Clinical Investigation.

“We looked at precancerous lesions on patients with sun-damaged skin,” said Washington University dermatologist and study co-author Lynn A. Cornelius, MD, director of the Division of Dermatology. “Most commonly found on the face, scalp and arms, these lesions appear abnormal by visual examination and under the microscope but are not full-blown skin cancers. But because these lesions have the potential to develop into a true skin cancer, they are commonly treated. Our study shows this combination therapy is more effective and better tolerated than current treatment practices.”

On average, the investigational therapy reduced the number of precancerous skin lesions on the face by almost 88 percent compared with a 26 percent reduction using the standard chemotherapy. While some side effects such as skin scaling and itching were similar with both treatments, patients receiving the investigational therapy reported more redness and increased burning sensations, which are consistent with the immune response it triggers. Interestingly, although not specifically measured, patients who had been treated previously with conventional therapies reported decreased pain and discomfort with the combination treatment, according to Cornelius, who is also the Winfred A. and Emma R. Showman Professor of Dermatology.

The investigational treatment combines a cream formulation of a chemotherapy drug called 5-fluorouracil with a synthetic form of vitamin D called calcipotriol. Topical 5-fluorouracil alone is prescribed to treat actinic keratosis. Calcipotriol is approved by the Food and Drug Administration (FDA) for treatment of psoriasis, an autoimmune disorder characterized by red, scaly patches of skin.

Past studies of mice prone to allergic inflammation, especially eczema rash on the skin, have shown that they also are resistant to developing skin cancer. These observations suggested that overreactive immunity triggered by damaged skin may have a beneficial side effect — a hyper-vigilant immune system that also attacks any cancerous cells that may form. Earlier work at Washington University by senior author Shadmehr Demehri, MD, PhD, now at Harvard Medical School, showed that a protein called TSLP in the skin activates the immune system’s T cells, which then attack tumor cells. Calcipotriol also was known to cause the skin to produce TSLP.

“The idea behind this study was to induce a heightened immune response in the skin using calcipotriol combined with the 5-fluorouracil that works to destroy the precancerous cells,” Cornelius said. “In so doing, the destroyed precancerous cells release cell proteins, or antigens, and facilitate the heightened immune system to respond. We compared the two-drug formulation to 5-fluorouracil alone over a shorter application period — four days as opposed to two to four weeks that is typical for the standard treatment of 5-fluorouracil alone.”

The current study involved 132 patients with actinic keratosis treated at Washington University School of Medicine in St. Louis. Sixty-five of these patients were randomly assigned to receive the investigational drug combination of 5-fluorouracil plus calcipotriol. The remaining 67 served as a control group and received the standard 5-fluorouracil plus Vaseline petroleum jelly. Patients applied the assigned cream twice daily for four days.

Patients in the investigational and control groups began the trial with similar numbers of precancerous lesions on each part of the body examined. At each body site evaluated, there were on average about 15 lesions on the face, 22 lesions on the scalp, 14 lesions on the right arm and 12 on the left arm. Following treatment, facial lesions were reduced by 88 percent in the investigational group versus 26 percent in the control group. On the scalp, lesions were reduced by 76 percent in the investigational group compared with about 6 percent for the control group. On the right arm, the reduction was 69 percent for the investigational treatment versus about 10 percent for the control. On the left arm, the precancerous lesions were reduced by 79 percent for the investigational treatment compared with 16 percent for the control.

“Because calcipotriol has been shown to induce an immune response, we are now interested in seeing if the anti-tumor immunity of the activated T cells can be recalled later to help prevent both precancerous and cancerous skin lesions,” Cornelius said. “We are now planning to re-contact our patients to determine whether there are differences in precancerous and skin cancer rates between the two treatment groups.”