Chemopreventive agents being explored could protect skin from developing cancer

Miami Beach, Fla. - Efforts to prevent and chemoprevent melanoma are ongoing, and though much still needs to be done, one expert says some inroads are being made that may impact mortality, morbidity and quality of life.

“Dermatologists are in a unique position to be able to lead the field of chemoprevention because there is no other cancer that is as detectable and accessible without the use of specialized diagnostic tests as melanoma,” says Sancy Leachman, M.D., director of the Melanoma and Cutaneous Oncology Program and professor of the department of dermatology, University of Utah School of Medicine, Salt lake City.

With the current epidemic of melanoma, the primary and secondary prevention methods in place are more important than ever to help reduce the incidence of the disease. Though still in its infancy for melanoma and skin cancer however, the concept of chemoprevention is turning heads, particularly in the dermatologic community.

For years, dermatologists have been practicing a form of chemoprevention, Dr. Leachman says, by treating actinic keratoses with agents such as 5-fluorouracil and imiquimod in order to prevent development of squamous cell carcinoma. According to Dr. Leachman, who spoke at the American Academy of Dermatology annual meeting, such preventive treatments could serve as a model for development of melanoma prevention agents as well.

Skin test

In terms of chemoprevention, dermatologists have an advantage in their ability to biopsy skin to determine whether a potential chemoprevention agent is having the intended effect on the target skin cell. Unfortunately, however, Dr. Leachman says the chemoprevention agents that have been explored to date have not completely gone through a rigorous scientific vetting process to show a high likelihood of succeeding while still being safe for the patient.

“The bar for treating someone preventively is much higher than for treating someone therapeutically,” she says. “If you treat someone therapeutically, they have a problematic condition that warrants therapy, but in treating someone who has not yet developed the condition, the ‘do no harm’ philosophy is paramount.”

Melanoma is one of only a few cancers with a strong environmental component, namely ultraviolet (UV) light. According to Dr. Leachman, this knowledge gives dermatologists the unique opportunity to target a UV light event (such as a beach vacation), selectively using a chemoprevention agent at the time when patients expose themselves to UV light. This is an advantage relative to chemoprevention agents that must be given on a daily basis, because it reduces the possibility of adverse side effects.

“A pulse therapy given at a set time before, during and after UV environmental exposure could be an ideal chemoprevention solution for individuals that have a predominantly indoor occupation,” Dr. Leachman says. “However, for someone who is out in the sun every day, you might have to give a chemoprevention agent more often. This underscores the importance of the safety of chemoprevention agents.”

There are several different classes of potential chemoprevention agents that are being studied, she says, including N-acetyl cysteine, antioxidants, aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDS), and agents that enhance DNA repair, among others. The hope is that these agents can impact pathways to reduce mutations in the skin that lead to cancer.

Antioxidant analysis

Though antioxidants have been extensively studied in other cancers in the past, Dr. Leachman says that historically, antioxidants that have been used for cancer chemoprevention - such as vitamin E and selenium in prostate cancer and beta-carotene and retinoids in lung cancer - have failed.

“Though the trials with antioxidants have failed so far, we need to persevere and find a way to overcome those failures. I believe that oxidative stress is one fundamental and targetable pathway responsible for skin cancer, particularly in melanoma,” Dr. Leachman says.

For an antioxidant to be truly effective as a chemoprevention agent, she says, the agent has to be able to raise the antioxidant capacity of the cell intracellularly, where it can reduce DNA damage. Some clinicians are currently treating their patients with antioxidants such as vitamin C and E, Dr. Leachman says, but these antioxidants may not be increasing the intracellular antioxidant capacity, which is necessary to make a difference.

On the contrary, Dr. Leachman says that although these antioxidants may decrease oxidative stress extracellularly, they could have a paradoxical negative feedback effect to reduce intracellular capacity to counter oxidative stress. This could explain the previous failures of antioxidant prevention strategies.

“DNA damage plays a central role in skin cancer development, so agents that can increase the capacity of the cell to repair DNA are strong candidates for chemoprevention,” Dr. Leachman says.

Testing for success

Other chemoprevention agents that could be effective are those that may be able to artificially - without the damage due to the sun - increase the tan of the skin, such as the melanocortin-1 receptor agonists. These agents can not only lead to increased pigment production and decreased damage but also increase repair.

According to Dr. Leachman, future research should systematically test each agent in a relevant animal model and demonstrate success, while at the same time, permit the design of biomarkers that can indicate whether a particular agent is having its intended effect on a pre-designated target. These biomarkers would need to be validated in a small phase 1 clinical trial, she says, to determine the potential of success of the studied agents before moving into larger chemoprevention trials, which would optimally be performed in a high-risk patient population.

“It is an exciting time on all fronts of melanoma prevention and I think we are in the position to be able to bring a truly effective and safe chemoprevention agent into existence. The hope is that these concerted efforts may ultimately culminate in helping our patients to avoid this horrible condition called melanoma,” Dr. Leachman says.

Disclosures: Dr. Leachman reports no relevant financial interests.

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