Problem:

When it comes to cancer patients with metastatic melanoma, there is little that can be done on their behalf. But for a few patients, studies are currently underway that could drastically improve their likelihood of survival.

How it all started:

The research began a few years ago when scientists in the Division of Anatomic Pathology in the Department of Pathology at the University of Utah were studying gastrointestinal stromal tumors (GISTs) with mutations in the c-kit gene.  KIT, the protein coded for by the c-kit gene, normally activates cellular signals which tell the cell to grow and divide. In most normal circumstances, the c-kit gene is turned off and KIT is silent. However, it was discovered that GISTs have mutations in the c-kit gene which result in a KIT protein that is activated, or in other words is always turned on.  Activation of the KIT protein causes a constant signal for the GIST tumor cells to grow. It has been discovered that GISTs, a tumor which previously had been therapeutically resistant, can be controlled by use of a new drug called Gleevec.  Gleevec works as a tyrosine kinase inhibitor that binds to the active site of the mutationally active tyrosine kinase KIT and inhibits the protein.  Inhibition of KIT stops cellular signaling and turns off tumor growth.  There are several different types of c-kit activating mutations occurring in GISTs and some are more responsive to Gleevec than others.  To aid in the treatment of GIST patients, it is now possible, through the research efforts in Anatomic Pathology, to determine the type of c-kit mutation in GISTs.
 
While developing molecular testing for GISTs, research indicated that mutational activation of another growth signaling protein, BRAF, was present in a large percent of melanomas. This prompted interest in developing mutational testing for BRAF in melanoma, similar to that developed for c-kit in GISTs.  One hundred and fifty melanomas were tested for BRAF mutation and the mutation was found in almost 50% of the tumors. Although initially there was no interest in testing for c-kit mutations in melanoma because the scientific literature at the time suggested that c-kit mutations in melanoma were unlikely, it had been known for years that normal functioning of c-kit is necessary for melanocytic development. Could some melanomas have c-kit mutations similar to those observed in GIST? With 150 cases of melanoma at their disposal, scientists in Anatomic Pathology would be able to answer this question.
 

Breakthrough:

When the melanomas were tested for c-kit mutations, surprisingly, 3 of the 150 melanomas were positive. Because c-kit mutation positive GISTs respond to Gleevec, this suggests that these c-kit positive melanomas might also respond. This exciting work was published in the journal Human Pathology in 2006.  Since that time, other groups have also reported c-kit mutations in melanoma. Remarkably, there seems to be a location preference for those tumors which have c-kit mutations. Melanomas arising in sites that receive chronic sun damage like the head and neck as well as mucosal melanomas have a higher percentage of c-kit mutations than those arising on the arms and trunk.  Clinical trials are currently underway in Boston and New York to determine if patients with c-kit mutation positive melanomas respond to Gleevec. 

What This Means for the Future:

Even though melanomas look the same under a microscope, we are beginning to explore the idea of molecular heterogeneity and site of origin.  If melanomas can be sorted by location and mutation, treatment will become more specialized and personalized to the patient, hopefully increasing the success of eradication and recovery.  Drs. Holden and Layfield in the Division of Anatomic Pathology, along with their colleagues, are excited about this area of research and we are all looking forward to the results of the clinical trials to determine the activity of Gleevec in patients with c-kit mutation positive melanoma.