Poulikos Poulikakos, PhD, from Mount Sinai Hospital, discussed his work in MAPK signaling, as well as the future of treating patients with melanoma by combining targeted therapy and immunotherapy, at the 16th International Congress of the Society for Melanoma Research (SMR), held November 20-23, in Salt Lake City.
So, I find these types of meetings extremely important and useful to bring together the clinicians, clinical researchers, and basic scientists like me. I feel that has contributed a lot, and tremendous progress we have seen maybe the last 10 years in the melanoma field. And I’m looking forward to more meetings like that. (There are) maybe about 2 (melanoma meetings) a year like this, and I hope there will be actually more. So, the clinical experience is very important when we’re trying to go back to the lab and try to understand mechanisms, try to understand tumor response to therapies, and so on. Sometimes we are isolated from that and the clinicians are isolated from that, these meetings are extremely useful because of that – bringing people together to discuss real problems in real life.
So, I think in general that we are now in exciting times when it comes to novel therapeutics and novel combination strategies to target MAPK signaling. So, my work in general is focused on small molecule inhibitors within the pathway of MAPK signaling. I presented some data on an exciting new target…There’s a couple of compounds that are now in clinical trials and maybe more that are coming in that (have not been studied) in melanoma…The second part of the talk had to do with some innovative work I think we do at the pre-clinical level by rationally combining RAF inhibitors that could bind to different formational states of the oncoproduct BRAF, which is very important in melanoma. But half of melanomas have these mutated form. And the last part of the talk was more about some more theoretical concepts and where we go from here. Definitely the future is combinatorial strategies, but not any combinations. Toxicities have to be addressed, that seems to be the major upcycle right now when we’re trying to combine different inhibitors. But if we understand the mechanism (of how) the inhibitor or the pathway works, I think we can combine (treatments for melanoma) rationally.
I’m (practice) at Mount Sinai in New York, we have a melanoma program there. I work there with the clinicians; we’re trying to put these ideas into practice. Either treat patients off-label, try to get some data from that, and maybe move on to clinical trials. To me, the major problem is we need to start designing clinical trials and the field is moving already there into this direction, but I wanted to emphasize we need to design clinical trials that we actually learn things from them, not just tumor response or toxicities, but look inside the tumor, look at target engagement, look at inhibition of the pathway, actually know and learn from any clinical trial, even if it fails. Why did it fail, is it the target not right, is it the drug is not good enough yet, we’ll have to make a better compound or go in a different way, so that’s always my thinking when I go back and I try to interact with clinicians, either at my institution, or other institutions.
It has been like 10 years in the melanoma field where 5-year survival in the metastatic setting (ranges from 5%-10%, but now we see rates of) 25%-30% with either RAF and MEK inhibitors with targeted therapies or immunotherapy. I feel we need to push forward in this direction, perhaps designing more rational combinations, or combining the 2 approaches, and again the toxicity isn’t the problem, we need to find maybe perhaps metronomic schedule alternating therapies to increase this level of survival. There’s a lot of talk on, which I find very interesting, on moving these therapies earlier to the adjuvant or neoadjuvant setting where they seem to be working really well, so I feel that 1 year from now we’ll have the data from combining the immunotherapy PD-1 antibody with RAF and MEK inhibitors and maybe that will now instruct standard care for melanoma. And in 5 years I hope we will have the data from moving earlier, from moving to neoadjuvant and adjuvant setting, maybe we will now have prolonged survival or almost cures for the majority of melanoma patients.