Melanoma and Mutations

Melanoma and Mutations

George W. Sledge, MD, FASCO

Feb 10, 2011

I am writing this while sitting in an airport lounge in Toronto. I spend a great deal of time sitting in airports this year. Yesterday I had the opportunity to meet our Canadian colleagues in the Ontario Institute for Cancer Research, an energetic and relatively new consortium of cancer investigators. They are currently having their 4th Annual Scientific Meeting at the wonderfully named Nottawasaga Inn. Now I am headed back home, with tomorrow's clinic awaiting me.

Being president of your Society has expanded my horizons, forcing me to think about the broader scientific agenda in our battle against cancer. This is a great time for those interested in cancer biology and its implications for cancer care. I've shared my thoughts on some of these in previous posts.  Today let's discuss melanoma.

After a generation of therapeutic nihilism, melanoma is suddenly a "hot" tumor, with two new therapeutic approaches showing promise in the past year. One of these, PLX4032, is a kinase inhibitor for B-RAF, and recent work suggests that it has significant activity and relatively minimal toxicity. As B-RAF mutations are relatively common in melanoma, this could have a significant impact in these terrible tumors.

But--there is always a but in oncology--responses do not last forever with this agent. Drug resistance is already raising its ugly head. What is striking, however, is that before we have had a public presentation of the first phase III trial, we already have a handle on resistance. Two back to back papers in Nature by Nazarian and Johannessen have, between them, already identified three separate mechanisms of drug resistance. These involve, respectively, upregulation of PDGFR-B, N-RAS mutations, and activation of COT (downstream of B-RAF in its activation pathway). And these are not just cell line phenomena, as the changes were seen in human tumors resistant to PLX4032. There are other mutations leading to resistance out there somewhere in the wind, waiting to be found--the authors of one of these papers were unable to identify the mechanism of resistance in half the resistant melanomas they studied.

Should we be depressed or excited by these findings? The answer is yes. Multiple mechanisms of resistance, with more in the offing, means that this is another smart cancer. Killing it will involve multiple separate combinatorial approaches. How many we cannot yet say. We do not yet have most of the tools needed to target the identified mutations driving resistance (though I am sure there are compounds on some shelf somewhere that inhibit them). We do not know whether the combinations needed will be toxic. And, as we subset and subset rarer diseases, the financial incentives to develop novel agents diminish. We currently lack the informed consent, clinical trials apparatus, and regulatory apparatus that would allow simultaneous tissue acquisition, testing, treatment, and approval of multiple combinations in a given population: we are stubbornly linear in an increasingly nonlinear world.

That is the bad news. The good news, as the Nature reports suggest, is that we can interrogate tumors in an almost real-time fashion for mechanisms of resistance, identify them, and demonstrate in vitro the path to reversal of resistance. This tells us how fast the technology is moving, and where we are headed in the next few years as personalized genomics informs the development of targeted therapy. I love this stuff.


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