Identification of a key player in a signaling pathway involved in the development of melanoma the deadliest form of skin cancer may offer hope for new targeted melanoma therapies.
Ann Richmond, Ph.D., and colleagues at Vanderbilt-Ingram Cancer Center report that a signaling molecule, known as IKKβ, is essential for melanoma tumor development in a mouse model of the disease. The results, published June 7 in the Journal of Clinical Investigation, also point to ways of targeting therapies that inhibit IKKβ toward the patients most likely to benefit from them based on their genetic profile.
Melanoma is the deadliest form of skin cancer and incredibly difficult to treat successfully once the tumor has spread beyond the skin.
Prior studies have shown that the NF-κB signaling pathway centered on the protein NF-κB, which regulates gene expression is abnormally activated in tumor cells; the pathway is turned "on" constantly, even at times it should be turned "off." This activation often results from abnormal activation of another enzyme in the pathway, IKKβ.
Just how NF-κB contributes to tumor progression has been unclear. And with drugs that inhibit this pathway entering clinical trials, a clearer picture of its function in tumor progression is needed.
To better understand the role of this pathway in particular, of IKKβ's role Richmond's lab developed a mouse model that mimics the genetic alterations involved in melanoma development in humans.
Jinming Yang, Ph.D., a staff scientist in Richmond's lab, led the effort to generate these mice, which lack the tumor suppressor INK4a/ARF (commonly lost in melanomas) and have the Ras/Raf pathway activated (which is activated in about 70 percent of melanoma lesions).
The researchers then added the ability to "turn off" IKKβ only in melanocytes, the pigment-producing skin cells in which melanomas initiate, simply by
|Contact: Dagny Stuart|
Vanderbilt University Medical Center