Pharma Strategy Blog

This is turning out to be quite a week for posts on interesting and new things happening in melanoma.

Source: Wikipedia: metastatic melanoma that has invaded the pancreas

Yesterday, we discussed novel mechanisms of resistance to BRAF inhibitors such as PLX4032 and tomorrow we will review new findings associated with MEK resistance, but today I wanted to draw your attention to more basic research, that is, the identification of a new mutation in melanoma.

In a fascinating Letter to Nature Genetics, Wei et al., (2011) described how they used exome sequencing to systematically look at alterations in the DNA seen in the disease in 14 matched normal and metastatic tumours:

“Using stringent criteria, we identified 68 genes that appeared to be somatically mutated at elevated frequency, many of which are not known to be genetically altered in tumors.”

This is crucial, because when we consider therapeutic intervention down the road, we want to find targets that are aberrant in cancer, but preferrably, do not exist in people without cancer.  The reason for this is that many unwanted side effects are reduced by having a clear and obvious target.

What did the research show?

According to Wei et al., (2011), they found

“We discovered that TRRAP harbored a recurrent mutation that clustered in one position (p. Ser722Phe) in 6 out of 167 affected individuals (~4%), as well as a previously unidentified gene, GRIN2A, which was mutated in 33% of melanoma samples.”

The emphasis is mine, but what I found interesting was that TRRAP may be a new oncogene and GRIN2A may offer a druggable target in the same way that BRAF currently does for BRAF inhibitors.

Now, there are some limitations to this excellent piece of research:

1. Small sample size
2. Extrapolation to a wider population cannot be assumed
3. Further research is essential to validate the targets

Implications:

The limitations aside, the findings are very important and do provide some useful clues for researchers to home in on and consider new studies to advance both the field, and our understanding of the biology of melanoma, further:

“Our study provides… the most comprehensive map of genetic alterations in melanoma to date and suggests that the glutamate signaling pathway is involved in this disease.”

This may a little bit of a surprise to the uninitiated.  Glutamate is an essential amino acid and a transmitter in the mature mammalian nervous system, but glutamate antagonists have been shown to limit tumour growth, as you can see in a PNAS article from Rzeski et al., (2001).

Overall, I think we will be hearing more about TRRAP and GRIN2A in metastatic melanoma going forwards.

References:

Wei, X., Walia, V., Lin, J., Teer, J., Prickett, T., Gartner, J., Davis, S., Stemke-Hale, K., Davies, M., Gershenwald, J., Robinson, W., Robinson, S., Rosenberg, S., & Samuels, Y. (2011). Exome sequencing identifies GRIN2A as frequently mutated in melanoma Nature Genetics DOI: 10.1038/ng.810

Rzeski, W. (2001). From the Cover: Glutamate antagonists limit tumor growth Proceedings of the National Academy of Sciences, 98 (11), 6372-6377 DOI: 10.1073/pnas.091113598