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Preclinical Study Evaluates p300 Protein in AR-Driven Prostate Cancer - Jie Luo

November 21, 2025

Zachary Klaassen speaks with Jie Luo about his Prostate Cancer Foundation Young Investigator Award work on androgen receptor enhanceosomes in prostate cancer. Dr. Luo explains that enhanceosomes are complex protein assemblies where androgen receptor binds to distant DNA enhancer elements and recruits co-regulators including p300, a histone acetyltransferase enzyme that triggers oncogene expression. His research demonstrates that p300 protein levels are dramatically elevated in prostate cancer tissues compared to benign tissue. Dr. Luo's team developed p300 degraders using PROTAC technology, which completely eliminate p300 protein rather than simply inhibiting its activity. These compounds demonstrate potent tumor suppression and regression in preclinical models with favorable safety profiles in animal studies. Future work focuses on developing dual-targeting approaches combining p300 and androgen receptor to restrict effects to prostate cancer cells while minimizing toxicity in normal tissues, with phase 1 clinical trials anticipated following additional safety validation.

Biographies:

Jie Luo, PhD, Post Doctoral Researcher, The University of Michigan, Ann Arbor, MI

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA



Related Content:

Targeting Histone H2B Acetylated Enhanceosomes via p300/CBP Degradation in Prostate Cancer - Beyond the Abstract

p300/CBP degradation is required to disable the active AR enhanceosome in prostate cancer.

Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer.
Read the Full Video Transcript

Zachary Klaassen: Hi, my name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center. We are at the 32nd PCF Scientific Retreat in Carlsbad, California. I'm delighted to be joined by Dr. Jie Luo, who is a research investigator at the University of Michigan. Today we're going to be talking about his Young Investigator Award from the PCF discussing AR enhanceosomes. Jie, thanks so much for joining us.

Jie Luo: Thank you. Thank you for having me today to describe my work about the AR Neo-enhanceosome, AR enhanceosome.

Zachary Klaassen: That's great. You guys, congratulations first of all on the award and you guys were selected to give updates on your work at the PCF Scientific Retreat. So just tell us just by background for our listeners, what's an AR enhanceosome? What does that mean? Why were you guys looking at that? Why were you targeting it?

Jie Luo: Okay, so before that we have to know that prostate cancer is a prototypical, enhancer-driven malignancies. So what is the enhancer? Enhancer is very special DNA element to regulate the gene expression. It's not like a promoter region which is located very close to the gene body. It usually enhances locating far, far away from the gene body itself. And the AR is a transcription factor, actually it is the master transcription factor or master oncogene driver for the prostate cancer. So AR potentially binds to the enhancer elements and then recruit a bunch of the different kinds of co-regulators including several enzymes or like histone modification readers and as well as the basic transcriptional machinery like RNA Pol II to regulate the oncogene or the target gene expression.

Zachary Klaassen: Excellent.

Jie Luo: So the AR enhanceosome actually is very complicated.

Zachary Klaassen: Yeah.

Jie Luo: It's basically composite with different kinds of the co-regulators, different kinds of enzymes and all these factors, proteins are going to collaborate with the AR to drive the downstream oncogene expression and then promote the prostate cancer progression.

Zachary Klaassen: I think your work is looking at targeting p300, CBP. Just take us through, you get this award a couple of years ago. What have you guys sort of been working on the last couple of years and what did you present at the PCF Scientific Retreat?

Jie Luo: Yeah, so our story begins with this protein called the p300. It's a histone acetyltransferase, so basically histone has different kinds of the post-translational modification. We can add different kinds of modification to the histone itself and then this kind of modification can highlight the histone and highlight certain chromatin regions and to tell all kinds of the co-factors has come here and then we can do something very bad to trigger the oncogene expression. So p300 is a key enzyme to regulate one kind of the histone modification called the histone acetylation, and then when p300... actually we start from the AR. So where AR bind to the special enhancer regions and then they're going to recruit p300 and then p300 going to do all kinds of the histone acetylation and then highlight the specific regions and then trigger the downstream, further trigger the downstream co-factors recruitment and as well as RNA Pol II recruitments and then trigger the oncogene expression. So our story speaking from the compare different kinds of the patient matched, prostate cancer tissues versus the benign tissues. Interestingly, we find out that the p300 protein levels dramatically increase in the cancer tissues.

Zachary Klaassen: I see.

Jie Luo: And as well as some kind of the p300 downstream substrates like H2BN terminal acetylation, it's also consistently increase a lot in the cancer tissues. So that's encourage us to further study the p300's role in the AR enhancer and as well as the p300 roles in the promoting the prostate cancer progression.

Zachary Klaassen: Excellent. And you guys, the target you have is now you have a target for it. We just came off of ESMO 2025, lots of exciting phase one trials. So from a clinical standpoint, how far away are we from the phase one trials testing this in a phase one?

Jie Luo: Yeah, so for targeting the p300 our lab and collaborate with other labs, we develop a very novel p300 degraders using the very cutting edge technology called a Proteolysis targeting chimeras (PROTACs). So this kind of degrader can effectively degrade the p300 protein levels. So it's unlike the other type of the small molecule inhibitor which can just partially inhibit the p300 activity because our drug is degrade the p300. So p300 protein is gone. So of course p300 activity or the p300 driving the downstream signal is completely gone.

Zachary Klaassen: I see.

Jie Luo: So our compound actually, we have done a lot of the in vivo efficacy study as well as the safety profile. We found that our compound is very safe.

Zachary Klaassen: Great.

Jie Luo: It doesn't increase or induce any evident toxicity. Also it's very potent in the many, many in vivo models, tumor models we have tested, definitely, it's very potent to suppress the tumor growth. And also in the certain models we see that even tumor is regressed means the tumor volume is even smaller than the original-

Zachary Klaassen: I see.

Jie Luo: ... the size. So this one is very close, actually I would say that this compound is clinical ready and we are keep doing some safety profile in even big animals like dog and monkey. After we get a perfect data or the good data, we probably can promote this compound to the phase one clinical trial.

Zachary Klaassen: That's great. So you kind of answered my next question was what's the next sort of steps in this? But it sounds like it's moving it through some bigger pre-clinical models into the phase ones. Is that fair?

Jie Luo: Yeah, actually we also have a follow-up study in terms of the p300 protein itself because p300 actually some studies show that p300 is still quite important for the normal tissues. So our concern is like if we use a degrader we're probably going to affect some normal tissue's functions.

Zachary Klaassen: Sure.

Jie Luo: So we don't want that kind of the toxicity or the potential side effects. So right now we kind of develop a very novel modality which can target a p300 and the AR together. And this going to restrict the toxicity or I will say the effect of the targeting p300 on the specific lineage, especially in the AR prostate cancer cells.

Zachary Klaassen: I see.

Jie Luo: So this kind of direction going to prove first it's very potent to suppress the p300 driven or p300 and AR driven the prostate cancer. Also, this going to be very safe, not going to affect any other normal tissues. This is our future direction-

Zachary Klaassen: Wonderful.

Jie Luo: ... we are pursuing.

Zachary Klaassen: That's great. Great job breaking down a very complex topic for our listeners. Any take-home messages or concluding statements?

Jie Luo: Yeah, so for our study I would say our study discovered AR enhanceosome or the AR neo-enhanceosome and it's very perfect. It's very good like a target for future, a therapeutic target for the prostate cancer and also our study find out the p300 is very important for the AR enhanceosome. So in terms of the target AR itself, instead we can target a p300 or maybe in the future some other like p300 and then we still can effectively shut down the AR program, AR activity and then we can achieve the very good efficacy to suppress the prostate cancer. Maybe we hope in the future we can see this compound in the real clinic application.

Zachary Klaassen: Wonderful. Congratulations again.

Jie Luo: Thank you.