Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. We are with UroToday at the PCF Scientific Retreat in Carlsbad, California. I'm delighted to be joined by one of the PCF young investigators, Dr. Jia Li, who is an associate research scientist at Columbia University to talk about NSD2 lineage plasticity and advanced prostate cancer. Dr. Li, thanks for joining us on UroToday.

Jia Li: Hi. Thank you, Zach, to give me the opportunity to talk about my work.

Zachary Klaassen: Absolutely. And congratulations on your work. This is what really drives the next set of targets and really moving it into the clinical realm. So before we get into your work, just bring us back to why lineage plasticity is important. Why it's something we want to avoid with advanced prostate cancer.

Jia Li: So yes, so people may be not familiar with the lineage plasticity. It's a term that you think a very simple word that is cancer cells ability to change, either adapt to environment or injury response to a treatment. So in the advanced prostate cancer, it's acquired ability.

Zachary Klaassen: I see.

Jia Li: What is acquired is that after androgen receptor signal inhibitor treatment, so such like enzalutamide, the most popular. So this cancer cell just develop the ability, they do not change their genomic DNAs. It's not like you see that this COVID variant during the pandemic due to mutations. But this is not genomic change. It's epigenomic.

Zachary Klaassen: I see.

Jia Li: Which means that you are going to change the histone modifications, the methylation, or the chromatin remodeling. So all this epigenomic reprogramming process can change the cellular identities, but this is detrimental to the treatment because, you see, this cancer cell change their identity. They develop this ability that do not rely on the androgen receptor for the cellular growth anymore. So therefore, they quickly progress to novel variants. What is novel variant? They become another type of cancer like neuroendocrine tumor, like androgen receptor low, or they become androgen receptor and then neuroendocrine double-positive prostate cancer or androgen receptor and then neuroendocrine double-negative prostate cancer. All these variants are so aggressive, leading to the failure of this androgen receptor signal inhibitor treatment failure. So that's why that we have to avoid this lineage plasticity in advanced prostate cancer.

Zachary Klaassen: That's a great explanation because I think for people that treat prostate adenocarcinoma, we know neuroendocrine is sort of the end of the line. There's a lot of work going in to clinical trials and that, but it all comes back to the lineage plasticity, right?

Jia Li: Yeah.

Zachary Klaassen: So again, you presented, at the Young Investigator Symposium, an update of your work looking at NSD2 targeting. Maybe just take us back over the last couple years, what you guys have done with your YI award.

Jia Li: So after I win this YI award, I started to investigating testing variants of NSD2 inhibitors. So first, I compare their ability to inhibit their targets. That is a histone modification H3 lysine 36 dimethylation, whether these inhibitors be effective in vitro and whether they can really work to reverse lineage plasticity on the cellular level.

Zachary Klaassen: I see.

Jia Li: And also, I do some mechanism studies because they are all foundations from the successful clinical trial, I think. And also because I first did the genomic studies first, so that is used CRISPR-Cas9 to knockout NSD2. So I know how to reverse lineage plasticity. It's definitely a long-term treatment. It's not like 24 hour or 48 hour, you can get immediate effect. It's not like that. You knock out this gene, you up-regulate the other gene. It's not like that. That is what's in people's mind, the chemical reaction.

This is a long-term modulation, rewiring the whole lung process. And then because I told you that I use the genomic approach first, so I know how to reverse. So what I did for the inhibitors is to find the optimal conditions to reverse. And the most important is after this inhibitor treatment, after you reverse, I need to combination with enzalutamide.

Zachary Klaassen: I see.

Jia Li: So you have to find the optimal conditions. That's why I tried variants of condition and find that 21 days the key. That you treat these inhibitors for 21 days and after that, your combination with enzalutamide.

Zachary Klaassen: I see.

Jia Li: That's what I did during my YI work.

Zachary Klaassen: That's great. So from a simplistic view, if you're able to reverse lineage plasticity by targeting NSD2, presumably you make it AR receptor targetable again. Is that correct?

Jia Li: Yes. But what I observed is that not every time you can see really AR is up, but actually the signaling, the real activity... I mean, the whole pathway is active at this moment.

Zachary Klaassen: I see.

Jia Li: So that's why we optimal conditions is to the endpoint that combination with enzalutamide. That's why 21 days is a key moment.

Zachary Klaassen: I see.

Jia Li: At this moment, you started combination therapy.

Zachary Klaassen: I see. That's great. So we were just talking before we started recording that. This is in phase one now. So maybe tell us about that. We're starting to hopefully get this into the clinical setting. Is that true?

Jia Li: Oh, yes. So there is a company they called K36. So I think it's 2022, they developed novel orally available NSD2 inhibitor.

Zachary Klaassen: I see.

Jia Li: Orally available is important, right?

Zachary Klaassen: Yeah.

Jia Li: So this inhibitor is enrolled in a phase one in a multiple myeloma. That's their main focus at that time. And then, so I think that trial works very well actually. So that drug works. And this year, the most important this year on July 28th, they started phase one. They developed another inhibitor like KTX-2001. So this inhibitor is now enrolled in a phase one clinical trial to treat metastatic castration resistant prostate cancer.

Zachary Klaassen: Wow. That's great.

Jia Li: This is great news to me that is in phase one now. And yeah.

Zachary Klaassen: That's so exciting. You take an idea, you figure out what to target, you optimize the timing and now we're in a phase one trial.

Jia Li: Yeah.

Zachary Klaassen: Wonderful.

Jia Li: And the most important I figured out. So when they do the trial, they use 21 days. I feel like-

Zachary Klaassen: You're proud of that, weren't you?

Jia Li: Very proud.

Zachary Klaassen: You should be. That's awesome. So from a basic scientist translational standpoint, what other stuff are you working on? What sort of the future look like?

Jia Li: In the future, if I am independent, have my own lab, I want to do two things. The first is, of course, I'm going to continue translation this NSD2 inhibitor and AR inhibitor therapy into clinical use. Because there's still a lot of things to do because how the cancer cell maneuver this revolving process. You know that they revolving into the AR positive stage and they respond to enzalutamide. But what happened in the middle, you don't know. So we have to review the mechanism. So that is very critical for your accurate clinical trial success. And also maybe you can identify some novel targets that we can facilitate this combination therapy. And also, we need to identify the biomarkers that which patient group can respond to this combination therapy. These are all critical translational work, but the most important, I'm most fascinating is to study the fundamental mechanism of lineage plasticity.

Jia Li: I just talk with your colleague about my background. So I'm a stem cell biologist background actually. I work on the embryonic stem cells. That is the most classic plasticity. They differentiate. They become your heart, they become your kidney, they become your neuron in the brain, but then I stuck there. As a biologist, I stuck there. That's why when I jump into the cancer, I don't know what to align with my background. And when I see this lineage plasticity, I say, "Okay, that's what I'm going to do."

Zachary Klaassen: This is the combination. Yep. Yeah.

Jia Li: This is alignment.

Zachary Klaassen: This is alignment. Exactly. Well said.

Jia Li: I find my feet and the goal just let me go to this trajectory. My research just align each other. So in the future, I'm going to find the fundamental mechanism of lineage plasticity. So I'm going to use variety of ways to study how this cancer can do this. It's very hard for normal stem cell, but it's so easy for cancer, how they do it and what kind of condition can affect this more effectively. Maybe in one day I can just like a feedback. When I study in the cancer, I can feed back to the therapeutic stem cell, right?

Zachary Klaassen: Sure. Yep.

Jia Li: That's what I'm going to do in the future.

Zachary Klaassen: I love it. It's been great talking to you. Congratulations on this just wonderful work. And I think this is the beauty of partnering with basic science, translational science, moving into phase one studies. Trying to make it better for prostate cancer patients. So couple take home messages. Anything to conclude for our listeners?

Jia Li: I think that for the scientists that what you wish is to see one day this NSD2 inhibition, AR inhibition therapy can be applied in the clinic, really, really treat patient, to treat advanced prostate cancer. So it's like you have a vision and one day your vision become a reality. That is the most exciting moment from the scientist.

Zachary Klaassen: That's wonderful. No, that's great. Congratulations again. It was great to chat with you on UroToday. Thank you, Jia.

Jia Li: Thank you.