CHICAGO – In the not-too-distant future, dermatologists may be sending patients to the beach with a bagful of chemoprevention tricks to outwit ultraviolet radiation and reduce the risk of sun-related skin cancers.
“In addition to sunscreen, we'll be using these chemopreventive agents not only to reduce histologic response to ultraviolet light, but to repair the DNA damage that occurs as a result of overexposure to the sun,” said Dr. Craig Elmets. “Instead of sending patients to the beach covered up with long pants, long sleeves, and a hat, we can send them off to engage in their normal behavior with less worry about the long-term consequences.”
Sunscreens remain the first line of defense against cancer-inducing ultraviolet radiation, but they need backup, said Dr. Elmets, professor and chair of the department of dermatology and director of the Skin Disease Research Center at the University of Alabama, Birmingham. “They are greasy and messy, and people don't really enjoy applying them. And most people don't use nearly enough to achieve the sun protection factor stated on the label; in fact, studies show that most people only use about 25% of the necessary amount.” Sunscreens also have limited effect, he said. “Over a 5-year period, sunscreens will reduce squamous cell carcinomas by about 35%, but they have very little effect on basal cell carcinoma.”
A number of agents being investigated for the chemoprevention of skin cancers have shown promising results in both animal and human studies.
Dimericine is a form of the bacterial enzyme T4 endonuclease. When encapsulated in a liposome and applied topically, the compound appears to boost the body's DNA repair response by increasing base excision repair, Dr. Elmets said.
A 2001 study allocated 30 patients with xeroderma pigmentosum to dimericine or placebo for 1 year, in addition to sunscreen. Patients in the active group had a 68% reduction in actinic keratoses and a 30% reduction in basal cell carcinoma (Lancet 2001;24:926-9).
Dr. Elmets is the lead investigator in one of two ongoing dimericine trials. The first is a phase II study randomizing kidney transplant patients with nonmelanoma skin cancer to the drug or placebo for 12 months, with an outcome of new nonmelanoma skin cancers. The second, a phase III study, aimsino recruit up to 30 patients with xeroderma pigmentosum who will be allocated to dimericine or placebo, with the primary end point of new actinic keratoses.
“Another exciting molecule that may have good chemopreventive potential is GDC-0449,” Dr. Elmets said. The compound is a systemic hedgehog pathway antagonist. “The hedgehog pathway is an important regulator of cell growth and differentiation during embryogenesis. But mutations are associated with basal cell carcinomas in both children and adults,” he said. Animal research has shown that inhibiting this pathway can reduce tumor growth.
In a study ofi33 patients with metastatic or locally advanced basal cell carcinoma who took the drug at different doses,. 18Eachieved a response; 2 were complete and 16 were partial. Disease stabilized in 15 patients and progressed in 4 (N. Engl. J. Med. 2009;361:1164-72).
Twenty-four trials, in progress or recruiting, focus on GDC-0449's safety and efficacy in a variety of cancers, including basal cell nevus syndrome, and pancreatic, gastrointestinal, lung, breast, and brain cancers.
DMFO (alpha-difluoromethylornithine, also known as eflornithine) irreversibly inhibits ornithine decarboxylase, an enzyme unregulated in many tumors. In a recent phase III trial of 219 patients with a history of nonmelanoma skin cancer, there was no significant difference in the total numbers of nonmelanoma skin cancers between the active and placebo group after 4-5 years of follow-up (more than 1,200 person-years). But new basal cell carcinomas were 33% less common in the active group than in the placebo group (Cancer Prev. Res. 2010;3:35-47).
There are 20 active or completed trials looking at this agent in relation to several cancers, including bladder, GI, neuroblastoma, and trypanosomosis.
The cyclooxygenase-2 inhibitor celecoxib is also in the skin cancer race. “COX-2 is dramatically upregulated in actinic keratoses and squamous cell carcinomas, and also in the interstitial space around basal carcinoma tumor islands,” Dr. Elmets said. “When given orally, it inhibits COX-2 expression, reducing the prostaglandin E2 production implicated in skin cancers.”
A recent study of 60 patients with basal cell nevus syndrome treated with celecoxib found that those with less severe disease had a 20% increase in the number of basal cell carcinomas over 24 months, compared with a 50% increase in those taking placebo (Cancer Prev. Res. 2010;3:25-34).
Finally, Dr. Elmets said, an ancient and familiar drink holds intriguing possibilities. The primary catechin in green tea, EGCG, (epigallocatechin-3-gallate) is a potent antioxidant that appears to reduce histologic and clinical damage from exposure to ultraviolet lights A and B. “When ECGC is applied topically or given to animals to drink in their water, they show a dramatic reduction in new skin cancers. In humans, it reduces UVA and UVB erythema,” he said.