PHILADELPHIA – Treating precancerous skin lesions with topical targeted therapies may significantly reduce their size and inhibit the growth of cutaneous squamous cell carcinoma, the second most common form of cancer, suggests a new animal model study from the Perelman School of Medicine at the University of Pennsylvania. Notably, the two treatments – small-molecule kinase inhibitors known as dasatinib and BEZ-235 – were associated with fewer side effects compared to 5-fluorouracil, the first-line topical agent that destroys precancerous and cancer cells but is known to have adverse side effects. Researchers published the results in the Journal of Experimental Dermatology.
“The findings represent a promising and much-needed alternative to today’s topical therapies, one that directly targets the biological mechanisms driving the tumor’s growth,” said John T. Seykora, MD, PhD, an associate professor of Dermatology and senior author of the study. “With the number of cases of cutaneous squamous cell carcinoma steadily rising, it’s important we work to identify safer, more precise therapies to treat these cancers before they progress and spread. We believe these kinase inhibitors are potential candidates that warrant further study.”
Lesions known as actinic keratoses and squamous cell carcinoma in situ are known precursors to cutaneous squamous cell carcinoma. Every year, 700,000 new ones are reported to dermatologists in the United States, which incur treatment costs of about $1.6 billion. Today, many of the topical drugs used to treat them include 5-fluorouracil, imiquimod, diclofenac, and ingenol mebutate, but these agents have limitations. Some cause inflammation, have suboptimal results, or are very costly.
In a separate, related investigation, the topical kinase inhibitor known as KX2-391 was shown to be safe and effective in phase III clinical trials recently, but this Penn research is the first to compare the inhibitor to current standard of care.
The Penn team tested the efficacy of dasatinib, BEZ-235, and 5-fluorouracil using a transgenic mouse model in two separate experiments. In this model, the skin cancer shows activation of Src-family tyrosine kinases and downstream signaling pathways, including PI3K/mTOR, Ras/MAPK, and JAK/STAT, which are known drivers of the cancer in humans, making it a useful tool to screen kinase inhibitors.
Researchers measured the size of the lesions and took biopsies of treated mice and controls to assess tumor regression, inflammation, and epidermal ulcers at designated time points over a five-week time period.
Overall, topical dasatinib induced regression of the cancer similar to topical 5-fluorouracil but with less inflammation and no ulcers. Dasatinib applied daily to mice induced 45 percent and 77 percent regression of cutaneous squamous cell carcinoma after two and five weeks of treatment, respectively, compared to controls. 5-fluorouracil induced 70 percent regression at two weeks in eight mice; however, it was associated with epidermal ulcers in two out of 15 of the tumors observed, and seven of the eight mice in that group died. No ulcers or deaths were observed in the dasatinib or control groups.
Inflammation was determined by counting CD3-positive T cells and neutrophils – immune cells that respond to inflammation – at the treatment site. Dasatinib did not increase levels of CD3-positive T cells or neutrophils, while 5-fluorouracil induced inflammation and was associated with higher numbers of CD3-positive T cells and neutrophils compared to dasatinib-treated mice, the researchers report.
In a second experiment, the researchers found that BEZ-235, known to inhibit the PI3K/mTOR pathway in cancer, acted similarly to dasatinib. The treatment induced regression of the cancer by over 60 percent compared to control lesions at five weeks without significant inflammation or ulcers.
“Together, these data suggest that topical application of small-molecule kinase inhibitors may be useful for treating cutaneous squamous cell carcinoma and related precursor lesions,” Seykora said. “These data also raise the possibility that topical application of multiple small-molecule kinase inhibitors together may be more effective than a single compound.”
Study co-authors include Xiaoping Yang, Aliaa E. M. Daifallah, Shiela Shankar, Jacob Beer, Christine Marshall, Tzvete Dentchev, Francesca Seykora, Sebastian D'Armas, Jaeyi Hahn, Vivian Lee Hanan H. Sabry, and Assem M. Farag.
The work was supported by the Perelman School of Medicine and the National Institutes of Health (P30-AR069589 and RO1 CA-16583).
Editor’s note: Seykora and the University of Pennsylvania are co-owners of U.S. patents outlining the use of topical small-molecule kinase inhibitors to treat skin cancer. These patents have not yet been subject to a licensing agreement.
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