The Mole: What prompted you to conduct this study?
Dr. Lizzul: Skin cancer of the nonmelanoma type (i.e., squamous cell and basal cell carcinoma) is the most common skin cancer and is most often a result of sunlight exposure. Ultraviolet B light is believed to be mostly responsible for these cancers. Many squamous cell skin cancers are curable if detected early. However, many people still suffer from these cancers and some also die from them. Actinic keratoses are precancerous skin tumors that mainly result from long-term sun exposure in susceptible persons. They have the potential to progress to squamous cell carcinoma. Finding effective methods of preventing UV-induced cancers and precancerous lesions would have a major impact on the total amount of human cancer.
Image courtesty of Icey, ClockworkSoul via wikimediacommons
The Mole: Could you briefly explain your hypothesis?
Dr. Conney: In studying the effect of tea on UVB carcinogenesisis in an animal model, we found that caffeine was the major active constituent, and that pure caffeine inhibited carcinogenesis in this animal model. Topical caffeine was also active. Topical caffeine inhibited carcinogenesis in mice pretreated with UVB with a high risk of skin cancer in the absence of further UVB. Mechanistic studies showed that caffeine enhanced apoptosis (programmed cell death) in UVB-treated epidermis and in tumors. We hypothesize that topical caffeine will inhibit proliferation and stimulate apoptosis in the actinic keratoses.
Dr. Lizzul: The hypothesis to be tested in this study is that treatment of actinic keratoses with caffeine for 2 weeks will enhance apoptosis and inhibit the growth of these skin lesions in humans. The purpose of this study is to determine the effects of topical applications of caffeine on apoptosis (programmed cell death), proliferation, and the ATR/Chk1 pathway in actinic keratoses in human skin in vivo.
Our collaborators at Rutgers University found that treatment of UVB-pretreated high-risk mice with caffeine topically once a day, 5 days a week for 18 weeks inhibited the formation of keratoacanthomas and squamous cell carcinomas, decreased the size of the tumors, and enhanced apoptosis in the tumor. In an additional study, they found that treatment of high-risk mice topically with caffeine once a day for 3 or 14 days enhanced apoptosis in focal hyperplastic areas of the epidermis but not in diffuse hyperplastic areas.
We anticipate that most keratoses will have evidence of DNA damage and a p53 mutation and that treatment of the keratoses with caffeine for two weeks will stimulate apoptosis substantially and have a smaller inhibitory effect on proliferation. If our hypothesis that topical applications of caffeine to keratoses enhances apoptosis, this regimen may be helpful in decreasing the numbers of keratoses and inhibiting the formation of squamous cell carcinomas.
The Mole: Could you briefly explain the study protocol?
Dr. Lizzul: This is an investigator-initiated, randomized, double-blind, placebo-controlled trial of topical caffeine 6% vs. placebo for actinic keratosis.
The study visits will take place over four or five nonconsecutive days. A skin biopsy is conducted at study onset, then subjects will initiate treatment with topical caffeine or placebo at the study site.
They will be treating their lesions with either topical caffeine or placebo, three times daily for two weeks. Two weeks after the initiation of treatment, another skin biopsy is performed. A portion of the biopsy from the lesion will undergo diagnostic histopathology and the other portion will be evaluated for markers of proliferation and apoptosis. Saliva will also be collected from each subject before and after study cream treatment to detect salivary caffeine level by HPLC. Salivary caffeine levels will be used as an indicator of systemic absorption.
The Mole: Although this is a preliminary study, can you speculate on the eventual clinical implications of your research?
Dr. Lizzul: This study, if successful, will be a prelude to additional studies to determine whether topical applications of caffeine will inhibit the formation or cause regression of these lesions in high-risk individuals.
The Mole: What are the next steps for research on this topic?
Dr. Lizzul: In addition, a goal of this study is to develop additional information regarding possible health benefits of commonly used natural products, specifically caffeine, in the prevention and possible treatment of actinic keratoses, which may eventually progress to squamous cell carcinomas.
Moreover, once this phase I study in complete, and the data are analyzed, we would move on to a larger phase II study, with increased number of patients, a longer time period of treatment and follow up, and dose ranging exploration to identify an optimal time period and concentration of topical caffeine that would be used to treat actinic keratosis and/or skin cancers, such as squamous cell carcinoma (SCC), or even basal cell carcinoma (BCC).
Finally, it is important to recognize our co-investigator and chair of the department of dermatology at Tufts, Dr. Alice B. Gottlieb, as well dermatology resident Andrew Wang, and Tufts medical student Ari Goldminz, for their work.
—Heidi Splete (on Twitter @hsplete)