National report - Kinase inhibitors are the latest weapons in the cancer war, according to Mario Lacouture, M.D.
Accounting for 20 percent to 30 percent of the pharmaceutical industry's drug discovery programs, kinase inhibitors comprise the second-largest group of drug targets. Several kinase inhibitors are presently in clinical trials to treat skin cancer, making it imperative for dermatologists to understand how these drugs function and how to treat side effects, says Dr. Lacouture, an assistant professor of dermatology and member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.
The drug Gleevec (Novartis) is perhaps the most well-known kinase inhibitor. Approved by the Food and Drug Administration (FDA) in 2001 to treat chronic myeloid leukemia, it was the first cancer drug to selectively inhibit an abnormal protein expressed in cancer cells. The drug has a 90 percent remission rate, although some patients do develop resistance.
Gleevec's success prompted the drug industry to focus more closely on kinase inhibitors. Since 2001, the FDA has approved several others, including cetuximab, erlotinib and gefitinib to treat cancers of the lung and colon. In the area of melanoma therapy, more than 10 agents are now in either phase 1 or phase 2 clinical trials, Dr. Lacouture tells Dermatology Times.
One of the most notable drugs, he adds, is Sorafenib, manufactured by Bayer AG and Onyx Pharmaceuticals. The FDA approved the drug in December 2005 to treat renal cell carcinoma. However, studies suggest that the drug may also help treat melanoma. Among other cellular kinases, Sorafenib inhibits B-raf, which is mutated in about two-thirds of melanomas. Preliminary results suggest that the drug in combination with platinum-based chemotherapy may halt or shrink tumors in 33 percent of cases.
Also under way are clinical trials to treat other types of cutaneous malignancies. Epidermal growth factor receptor (EGFR) is over-expressed in a number of human tumors, including metastatic squamous cell carcinoma of the skin. Consequently, several companies are testing compounds that target EGFR.
But kinases are present in many other tissues, most notably the skin. EGFR is critical for normal homeostasis and integrity of the skin.
"Seventy to 90 percent of patients taking these drugs will develop cutaneous side effects," Dr. Lacouture says, including acneiform rashes, xerosis and hair and nail alterations.
"It's the new face of cancer therapy," Dr. Lacouture remarks. "Instead of the classic alopecia after chemotherapy, you're going to see a 40- to 50-year-old person with severe acne and long eyelashes and know that person has cancer."
While the effects may seem mild, they can disfigure a patient enough for him or her to decrease or discontinue treatment. Therefore, it is extremely important for dermatologists to recognize and treat these side effects of therapy, Dr. Lacouture says. Acneiform rashes respond well to oral antibiotics from the tetracycline family, or to topical calcineurin inhibitors.