Paraskevi Giannakakou, PhD, and her ARMA BIO co-founder Cheuk Man Cherie Au, PhD, are an XSeed Award Finalist team for work to develop a first-in-class small molecule that may defeat the drug resistance that many patients with advanced prostate cancer develop to standard-of-care anticancer medications. Giannakakou is Professor of Pharmacology in Medicine and Au is an Instructor of Pharmacology in Medicine, both at Weill Cornell Medicine.
The XSeed Award provides critical funding to translate scientific discoveries into commercially successful drug therapies. The 2024 XSeed awards will provide two winning teams up to $250,000 for New York City minority- and women-led life science and healthcare startups working on novel drug development projects. The winners will be announced in September 2024.
This conversation has been edited for length and clarity.
Cure: How did you get involved in this field and discover this novel drug target?
Paraskevi Giannakakou: Taxane drugs like docetaxel and cabazitaxel are standard chemotherapy drugs for men with advanced prostate cancer and target the microtubule cytoskeleton — the molecular scaffolding in cancer cells. Since graduate school, I have focused on the microtubule cytoskeleton and mechanisms of drug resistance.
When I looked at the prostate cancer literature, I saw that a protein called the androgen receptor (AR) is really driving the disease, and taxanes were the only chemotherapy drugs with clinical efficacy in this disease. I got the idea that the microtubule cytoskeleton might be involved in the import of AR into the cell nucleus. We discovered that taxanes keep AR in the cytoplasm, stopping it in its tracks and preventing it from getting into the nucleus where it would normally bind to DNA and activate its functions. So, AR is a secondary target for taxanes.
AR inhibitors such as abiraterone and enzalutamide are used often in prostate cancer treatment. They require a part of the AR called the ligand-binding domain. Despite initially responding to AR inhibitors, most patients progress and develop metastatic castration-resistant prostate cancer.
This progression occurs because prostate cancer cells can bypass the effects of AR inhibitors by producing AR splice variants. We have now developed a new compound that targets both AR and the most common of these splice variants, called AR-V7—a previously undruggable target that has posed significant challenges to traditional drug discovery.
Cure: How does this small molecule work against AR-V7?
Giannakakou: AR-V7 and other splice variants are overexpressed in prostate cancer. They lack the ligand-binding domain and confer resistance to AR signaling inhibitors and taxanes. That’s a big clinical problem.
When we delved into the biology of AR-V7, we discovered that it travels to the nucleus very quickly — much faster than full-length AR. We zoomed into the mechanism of AR-V7 nuclear import and determined it was distinct and potentially actionable.
After screening 170,000 small molecules, we identified a "molecular glue degrader" that quickly takes out both full-length AR as well as AR-V7. (Molecular glues are small molecules that bring together proteins to promote protein-protein interactions for degradation.) This is a unique mechanism of action. Our compound binds to both full-length AR and AR-V7 and recruits another enzyme to trigger their degradation.
Cure: Were you surprised by your findings?
Giannakakou: Targeted protein degradation is a very hot field. But for glue degraders, there's no way to rationally design them. We did not set out to design a molecular glue degrader. We landed on a molecular glue degrader, after performing very robust screens with very rigorous criteria.
Cure: What have your early findings shown about how well this new investigational drug may work?
Giannakakou: Our preliminary in vitro data show this compound overcomes enzalutamide resistance. We feel very strongly that it's going to be extremely beneficial for patients.
In early clinical studies, the compound will likely be evaluated in people with metastatic castration-resistant prostate cancer. But it also has the potential to be used earlier in the course of treatment for people with hormone-sensitive prostate cancer, who receive AR inhibitors as part of their standard care. We feel very hopeful and excited about what we know about this compound so far.
Cure: Do you think this agent would be used as part of combination therapy for men with prostate cancer?
Giannakakou: It's unlikely because this compound takes out AR altogether. Within four hours of giving the drug, full-length AR and AR-V7 are gone. The drugs abiraterone and enzalutamide require AR with the ligand-binding domain, and when my compound is used, there is nothing for them to act on. So, there may be no need to give other medications, which each have their own side effects.
Cure: You've been doing this kind of work for a long time. What keeps you going?
Giannakakou: The patients. Treatment resistance is the reason people with cancer die. They stop responding to whatever medications are available. Drug discovery is the epitome of this journey. I like the possibility of taking science from the lab and putting it into patients' hands to be useful.
Cure: If you win an XSeed Award, what would that mean for your research and your company?
Giannakakou: It would be huge because it would help us do vital experiments to facilitate the translation of the drug candidate to the clinic, including preclinical pharmacokinetic, toxicology, dose-finding and efficacy studies. These experiments are critical for us to reach the next pivot level for the company to attract Series A funding.
ARMA BIO would also greatly benefit from the opportunity to join the Cure drug accelerator space. The Cure ecosystem is remarkable, and we are looking forward to interacting with experts and learning a lot from them — benefiting from biotech expertise, drug discovery services and business insights. We also feel that winning the award would give us the opportunity to broaden our network through the Cure community. It would definitely accelerate the success of ARMA BIO.
Cure: Who is on your team?
Giannakakou: My coinvestigators are ARMA BIO co-founder Cheuk Man Cherie Au, PhD, Instructor of Pharmacology in Medicine at Weill Cornell Medicine, who also serves as Head of Research at ARMA BIO, and K.C. Nicolaou, PhD, CTO and Harry C. and Olga K. Wiess Professor of Chemistry at Rice University, the medicinal chemistry consultant to ARMA BIO.