A key player in a signalling pathway involved in the development of melanoma has been identified by scientists. This is a discovery that could offer hope for new targeted therapies for the deadliest form of skin cancer.
Dr. Ann Richmond, and colleagues at Vanderbilt-Ingram Cancer Center report that a signalling molecule, known as IKK_, is essential for melanoma tumour development in a mouse model of the disease.
The results, also point to ways of targeting therapies that inhibit IKK_ toward the patients most likely to benefit from them based on their genetic profile.
Prior studies have shown that the NF-?B signalling pathway - centered on the protein NF-?B, 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, IKK_.
Just how NF-?B contributes to tumour progression has been unclear.
And with drugs that inhibit this pathway entering clinical trials, a clearer picture of its function in tumour progression is needed.
To better understand the role of this pathway - in particular, of IKK_'s role - Richmond's lab developed a mouse model that mimics the genetic alterations involved in melanoma development in humans.
It was found that mice with normal IKK_ activity developed "loads and loads of melanoma tumors all over their bodies...on the tail, the ear, and anywhere melanocytes are," said Richmond.
But mice in which IKK_ was "turned off" developed no melanoma tumours.
They also found that treating mice with normal IKKB activity with small molecule inhibitors of the enzyme could inhibit the growth of melanoma lesions.
"This shows for the first time that you have to have IKK_ for Ras-induced melanoma, suggesting that there's a way to specifically target melanoma lesions," she said.
However, the experiments identified an important caveat- blocking IKK_ only seemed to protect against melanoma formation when another tumour suppressor, p53, is expressed.
Since mutations that disrupt p53 are sometimes found in melanomas, this suggests that therapies targeting IKK_ or the NF-?B pathway in general would need to be limited to tumours with normal p53.
The study is published in the Journal of Clinical Investigation.