Potential New Target for Melanoma Treatment Identified
Melanoma, a type of cancer that usually begins in the melanocytes (the pigment cells) of the skin, is notoriously resistant to chemotherapy and radiation therapy, leaving few treatment options once the cancer has metastasized.
Researchers from the Laboratory of Cell Biology in NCI’s Center for Cancer Research have identified a protein called SOX9 that both inhibits melanoma cell proliferation and restores the sensitivity of melanoma cells to the chemotherapy drug retinoic acid. The research team believes that these results, published March 9 in the Journal of Clinical Investigation, highlight SOX9 as a promising new target for melanoma therapies, and work is already underway to identify SOX9-directed agents to bring to early human trials.
The researchers had previously examined how SOX9 affects melanocytes’ response to ultraviolet B exposure and found that the protein plays a role in increasing skin pigmentation. “We put two and two together and figured that if SOX9 helps regulate the pigmentation and growth of normal melanocytes, maybe we should look at melanoma cells and see whether or not the SOX9 function was decreased, and if so, whether we could increase it and slow the cells’ growth,” said senior author Dr. Vincent Hearing.
The researchers compared SOX9 expression in normal human skin cells, nevi (moles, some of which can develop into melanoma), primary melanoma samples, and samples from metastatic tumors. While SOX9 was found in all of the normal skin samples, the protein was weakly expressed or missing in most of the nevi, in more than 90 percent of the primary tumors, and in all of the metastatic tumors.
When the researchers used gene transfer to restore SOX9 expression to melanoma cells grown in culture, the protein caused cell cycle arrest—the cancerous cells stopped dividing. In an ex vivo model of skin tissue with melanoma, in which normal melanocytes were replaced with cancerous cells, the introduction of SOX9 into the melanoma cells prevented them from forming tumors. Melanoma cells without SOX9 were able to form invasive tumors in the same skin model. Similar results were found when melanoma cells were injected under the skin of mice (subcutaneously)—untreated melanoma cells formed large tumors in the mice, while melanoma cells transfected with SOX9 grew poorly or not at all.
The researchers then looked for a way to restore SOX9 function in melanoma cells without gene transfer, which is currently an extremely difficult technique to use as a cancer treatment. They found that treating melanoma cells with a substance found naturally in the body called prostaglandin D2 (PGD2) increased the expression of SOX9 in the cells.
Treatment with either PGD2 or PGD2 plus retinoic acid inhibited the proliferation of melanoma cells by 50 percent and 75 percent, respectively. A drug called BW245C, which has been tested in humans for diagnostic purposes, is known to increase PGD2 levels in the body. When BW245C and retinoic acid were administered to mice with subcutaneous melanomas, “the combination…induced marked and significant decreases in tumor size” compared to tumors in mice that did not receive the drugs, explained the authors.
Dr. Thierry Passeron, lead author of the study and a dermatologist and researcher at the University Hospital of Nice, France, is currently exploring the use of other compounds—most of which are already used in humans—that may upregulate SOX9 expression. “We want to find the optimal combination to decrease proliferation and potentiate the effect of retinoic acid derivatives,” he explained. Dr. Passeron hopes to begin phase I clinical trials of a chosen combination beginning in 2011.