Dr. Ali Chomiak: Colorectal cancer is one of the second most commonly diagnosed cancers both in the US and across the world according to the World Health Organization. So, it's really a global issue that we're dealing with. And I will say that thanks to early detection and better treatment, we are getting better at reducing mortality rates from it, especially in the older population. The interesting and frustrating thing about colorectal cancer is that the rates are actually rising in young people and we don't know why.
Patrick Center: But here you are with your team with some real breakthrough research. You conducted trials with mice and there's this mimicking and I'll let you explain it. The idea that you can get the cancer cells to believe that they're being attacked by a virus or have a cold or something along those lines that opens them up to treatment.
Dr. Ali Chomiak: Exactly. So actually, most of our studies are in cell cancer lines, so we grow them in a dish. It's the quickest and easiest way to start studying these molecular effects. And you're right, what we use is, our project did this unique study where we did two different drugs that we know work separately and thought that they would enhance efficacy at each other at inducing what's called viral mimicry. And so, when we put them on the cancer cells in the dish, they basically cause the expression of some of these genes that make the cancer cells think that they're infected with a virus, that they have a cold, like you mentioned. And the good thing about this is that this wakes up the immune system. So, I don't know if you've heard the phrase of a, a cold tumor or cold immune tumor, it means it's hiding from your immune system. And so, this is a way for us to flag the cancer and say, “Hey, I'm here, I'm awake.” And for your own immune system to attack your own cancer cells.
Patrick Center: Where did this idea come from?
Dr. Ali Chomiak: So, my work at Northwestern was a little different. I was working on neuroviral developmental biology, but it got me connected to chromatin and my interest in epigenetics, which is the changes to the way your genome is regulated without actually changing the genome. And so that's where I came to Van Andel to study this process of targeting epigenetics, abnormal epigenetics to treat cancer. And so, this idea of the viral mimicry where we make it look like your cancer cells have a virus being expressed, even though they don't, that actually has been studied by many researchers at Van Andel and cancer epigeneticists at other universities. And it's really been done using one of the drugs we use. It's called a DNMT inhibitor, and it affects marksetters on your DNA without changing the DNA sequence. And so, we said, how can we make this work better? How can we make an even better viral mimicry or cold response in the cell? And that's when we added in this other, where my role came where I said, I want to make this work because although these drugs work in some types of cancers in humans, they're not really always efficacious. And so, we said, how do we improve this? And so that's where I came on. I said, I'm going to add this other drug that I think is going to make the first drug better. And lo and behold, in the cancer cells, in the dishes that we treat them on, it worked. And then this has been shown, not the viral mimicry part, but like you said, mouse models are very important. And some other labs have done some cancer studies in mouse models now using these drugs as well. And they seem to correspond with our results.
Patrick Center: So, what happens when you combine the two? You've mentioned the DNMT and you've introduced EZH2. Explain those two drugs and then what happens when you combine them?
Dr. Ali Chomiak: So actually, this is really important and an interesting part of our study, studying what these drugs do together. So, the DNMT inhibitors, they basically remove, it's called methylation on your DNA. So, one of these epigenetic marks that control how your genome is read. Almost like punctuation in a sentence. It changes which words are said and which words aren't said. And we found in humans and in cell culture that when you treat with these DNMT inhibitors, it causes another response in the cells. And so, if we are going to anthropomorphize the cells, they want to stay cancer cells. And so, when you treat with this one, a new epigenetic response emerges. And this is called, these are also methylation marks, but they're on histones, which is what your DNA is wrapped around. And so, we target that with the second inhibitor, the EZH2 inhibitor. So, it's this one, two punch to target two ways the cancer cell is trying to remain a cancer cell so we can open it up to this viral mimicry, to your immune cell recognizing it as cancer and attacking it and to the cancer cells dying.
Patrick Center: What is the next step, human trial?
Dr. Ali Chomiak: Great question. So, the unique thing about this project is that we're perfectly positioned to start a phase one clinical trial. Both of these drugs we're using, the DNMT inhibitor and the EZH2 inhibitor are separately FDA approved for different cancers outside of colorectal cancer. So, we already have an idea of their safety profile and their efficacy. And so now we're interested in starting a phase one clinical trial, testing them together, both to make sure they are safe together and to see if the efficacy we see in mice or in cancer cells translates into humans.
Patrick Center: Your findings have been published in Science Advances. I can only imagine your mind is always active. Are you already considering to enhance what you've already discovered?
Dr. Ali Chomiak: This is a great question. Yeah, science never sleeps. We end one project and continue on to the next. So now that this has been published, there are two directions we're going. One is initiating this phase one clinical trial. Van Andel's perfectly positioned for that. We have the Van Andel Stand Up to Cancer Epigenetics Dream Team which helps fund and initiate these trials. And then the other part that we're pursuing is following up on the molecular effects of these drugs. What are they doing in the cells? Exactly, we've talked about the epigenetics, but what the paper also revealed in addition to viral mimicry effects were some other new pathways coming up. One is calcium signaling seems to be playing a role in this. So, the next things I'm working on are asking how do these drugs work and what can we learn about them that can then go back. and help improve the clinical trials and their efficacy in patients.
Patrick Center: The use of AI is in its infancy. Scientific researchers are taking advantage of its power. Is VAI using it to discover and develop treatments?
Dr. Ali Chomiak: That's a great question. While my project didn't specifically use artificial intelligence, there are a lot of computing-based tools that went into this project. We do something called bioinformatics. And so, for a number of the experiments, we would collect a million data points you might say, and the bioinformatics, my co-author, Rochelle Tiedemann, she would then analyze these data points using high through computing to say what patterns do they tell us, what's happening in the cells. And then we don't do it as often but a lot of these drugs are discovered now through different programs that can model what a drug would look like interacting with a protein. Is this a potential target? And so that's where how some of the drugs that we use were discovered and more drug discoveries are occurring. Although our lab isn't doing it, a lot of labs are working on AI-based ways to diagnose or to, you know, it's called personalized medicine where you can look at features of a patient and their certain type of cancer and predict what they will respond to. Like we might say, would they respond to this drug combination we're proposing as a way to treat colorectal cancer. And that's way down the road, but this is the basic science research which gives them the data to start using those type of technologies. I'd like to highlight that, you know, you're talking to one scientist on it, but this project really entails many scientists, me and my co-author, who did the bioinformatics, and then Dr. Rothbart, whose lab I'm in, who organized the whole project. This study was funded both through Van Andel and an NIH National Cancer Institute grant called a SPOR. And this is a really cool funding mechanism that involves many different universities, including Johns Hopkins, the Coriell Institute, Indiana University, et cetera. And we all are working under this one funding mechanism to find epigenetic therapies to treat cancer. So really, this is a multi-person and multi-institute effort to try and find a solution to use epigenetic drugs to treat cancers.
Patrick Center: Is this a widespread approach, not just at Van Andel, but really in much of cancer research?
Dr. Ali Chomiak: There's a lot of collaboration across cancer research. This specific funding mechanism is a very prestigious one to earn. So not that many places have it. And Van Andel’s is very unique in that Van Andel’s and these other institutes with this specific funding mechanism, very unique in that it focuses on epigenetics.
Patrick Center: Dr. Ali Chomjak, thank you so much for your time.
Dr. Ali Chomiak: Thank you, Patrick.
