Kunal Rai, PhD, Discusses Genomic Alterations in Melanoma Therapy

Kunal Rai, PhD, from The University of Texas MD Anderson Cancer Center, discussed biological insights into melanoma and how genetic alterations may lead to specific therapies at the 16th International Congress of the Society for Melanoma Research (SMR), held November 20-23, in Salt Lake City.

Transcription:
It’s just like any other cancer, melanoma has many aspects to it which, in terms of biological insights into what part and how the melanoma progression happens and what the disease entails and how can we treat an individual with melanoma. So for that, the various aspects such as genomic makeup of the tumors, epigenomic makeup of the tumors, metabolic contents of it, and immune contents, as it becomes very obvious in the field now, and as one might have noticed, there is lots of talk and excitement about immune microenvironment in melanoma. So, now how does melanoma respond to specific therapies, the ones such as for example, BRAF and MEK inhibitors that have become quite popular and immune checkpoint blockade therapies, like anti-PD-1 and anti-CTLA4 therapies.

To understand which patients are going to respond or to understand how the treatment works, it’s important to get an understanding of various aspects of the disease. As I mentioned, how the genomics, epigenomics, metabolic, etc. So that’s why it’s important for this kind of conference to focus on various different aspects which together bring various experts and, in the end, the conclusions are made as to how, what are the advances that should be built up, which should be used for building the new treatment and therapies in melanoma.

So a conference like this helps quite a bit in the sense that we have experts that have traditionally focused on genomic aspects of melanoma, for example, BRAF mutation is absolutely critical, NRAS mutation and other subpopulation is very important, and a newer subtype such as NF-1 or Y-Type, triple Y-Type tumors. Now there are certain investigators that focus on how the genomic alterations eventually may drive to specific therapies. So for example in the session 1, there were talks on RAC mutation which is a relatively newer genetic aberration seen in melanoma, but it occurs only in the 5%-10% of melanomas, yet it’s important to know which therapies might be critical for these sort of patients that contain this RAC mutation. There were other talks on for example STK19 mutations and CDK13 mutations that now illuminate us on the new aspects of the biology, on new kinds of melanoma that can be, and how they can be treated. So that for example is one aspect. There was a session on epigenetics which allows you to learn what kind of new epigenetic therapies that could be used in melanoma that have actually not been utilized much at all in clinic. And then there is obviously lots of studies on how immune checkpoint blockade therapy works and how does the resistance to that therapy occurs, how the BRAF MEK inhibitors work, and what can we now add to them to get better responses.

The excitement for me comes from, for attending these conferences is that you can learn about new investigations that are going on in various aspects so basic biology of melanoma as well as all the other clinical outputs that are being seen in clinic. Obviously being at MD Anderson I’m close to seeing a lot of clinical developments, as well as some basic research. It’s always great to see what other investigators are doing at, in for example, in the very basic science using zebra fishes in models for example, to all the way to what happens in patients. So, for me, it’s the various aspects that are very exciting…Especially in the context where immune therapies have become so popular now and seems to be the future where we want to understand we can’t just use the mouse, I mean we’ve been using typically the mouse models, but at the end of the day human, there are various differences between human immune system and mouse and you want to be able to use human system in mice to be able to then use various therapies and understand what are their effects, and so I thought that was a really fantastic talk and something I’ll be looking forward to utilizing in my own research. And then, again, the last session on just what is being seen in clinic is also really fantastic in the sense of, because that allows us to now think about how to shape forward my research to have immediate clinical benefit at the end of it.

So, I talked about a basic systematic understanding of how epigenome changes drive melanoma progression, as well as how they are aberrant in response to PD1 therapy which is the most popular immune checkpoint therapy. So although we’ve gained a lot of understanding of the genetic aberrations in melanoma like BRAF, RAS, RAC, etc. we have limited understanding of epigenetic aberrations that occur in melanoma and how quickly we can utilize that for therapy because there’s a huge focus in pharma industry on getting new epigenetic inhibitors to clinic. But we have limited understanding of what epigenetic aberrations occur and if we can combine some of these new epigenetic inhibitors that are going to FDA approval in other diseases or in other clinical setting, to be able to combine with the PD-1 for example or BRAF MEK sort of therapy. So that’s the focus in my lab and I talked about the systematic integration of epigenomic integrations in PD-1 responders and PD-1 non responders and what we’ve found is that enhancers which are a certain kind of epigenetic elements that are now known to be aberrantly  activated in many different types of cancers are actually reprogrammed in response to PD-1 therapy and more importantly, certain enhancer makeup or this epigenomic makeup if you want to call it can actually dictate how whether the patient is going to respond to PD1 therapy or not. So we are very excited about that and we want to use that as a sort of biomarker in combination with other genetic events such as immune events such as T-cell infiltration to be able to combine them in a way to predict which patients are going to respond or not. So that was one part of my presentation and the other part of my presentation was focused on how we can now combine bromodomain inhibitors which are essentially an umbrella inhibitor for enhancers along with PD-1 to be able to get better responses in anti-PD-1 non responders. And in fact, I presented some data on preclinical models of melanoma that the combination of RET inhibitor plus PD-1 inhibitor does very well when combined in specific doses. So now we’re in talks with some of the pharma industry to be able to begin a clinical trial and we want to, we will be doing that really soon.

I think there is a lot of potential angles, one in terms of personalized therapy, so for example we’ve been focusing on BRAF mutation group mutant melanomas and RAS mutant melanomas and their specific standard of care therapies, however there could be smaller subsets such as RAC mutant melanomas and they could get certain therapies. So obviously from the side of personalized medicine there might be important advances that we could potentially take into clinic later on. What excites me is to look more into the clinical samples from the new trials that have begin through combining PD-1 plus BRAF-MEK inhibitors and looking at really what is the epigenetic makeup of those. We are also excited about obviously autoimmune trials in terms of combining epigenetic inhibitors with the PD-1. So there is a lot of learning, I was, I actually learned a lot about immune system and how immune system is helping the tumors grow or not grow in terms of, especially in the context of these immune checkpoint therapies, so my lab is quite focused on understanding the biology of the immune checkpoint focused therapy from epigenomic angle and I’ll be employing a lot of this in my work going forward.

Yeah, I think these meetings are really critical to get investigators in melanoma together to be able to, you know, make the progress forward. Otherwise you are in your own little lab or little own research area that you enjoy, which is great, and you make some progress, which is fantastic again, but to be able to come out and learn from others, and then include that in your research or to make further progress is I think critical and this was a fantastic venue for a meeting like this and I did my PhD in Salt Lake City so this was a great time for me to come back and relive some of the memories I had out here, so.