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Prostate Cancer Drug Candidate Developed at UTHSC Goes to First Clinical Trial

Drs. Duane Miller, left, and Ramesh Narayanan, have developed a drug candidate for advanced metastatic prostate cancer that is now in its first clinical trial and has received fast-track status from the FDA, potentially accelerating its clinical development.

Researcher Ramesh Narayanan, PhD, knows the odds.

The deputy director of the Center for Cancer Research and the Muirhead Endowed Professor in the College of Medicine at the University of Tennessee Health Science Center, knows that very few researchers are able to conceive and develop a drug candidate that makes it from the lab to clinical trials.

“If you take all the academic researchers in the United States, probably only an insignificant percent would have the luxury or the privilege of taking a drug all the way from concept to clinical trial,” he says.

Still, Dr. Narayanan and his collaborator, Duane Miller, PhD, Professor Emeritus in the Department of Pharmaceutical Sciences at UTHSC, have defied the odds. Their drug candidate, a molecule designed as a treatment for advanced metastatic castration-resistant prostate cancer, is now in its first clinical trial.

“This is a major milestone in my career and life,” Dr. Narayanan says. “This is a very, very rare occurrence.”

Biopharmaceutical company Oncternal Therapeutics, Inc., holds the license for the drug candidate, an androgen (male hormone) receptor inhibitor dubbed ONCT-534, developed at UTHSC by Drs. Narayan and Miller. On October 5, the company announced the first patient had received ONCT-534. On October 26, Oncternal disclosed that the Food and Drug Administration granted fast-track designation for ONCT-534, which could potentially accelerate the clinical development process.

“This is a major milestone in my career and life. This is a very, very rare occurrence.”

Dr. Ramesh Narayanan

Dr. Narayanan and Dr. Miller have worked for more than a decade on therapies involving the hormone receptors that influence cancer progression. Among their projects, they have focused on creating drug candidates that could extend the survival of patients with aggressive, advanced, or resistant prostate cancer.

 “We felt that there is a significant need for this patient population,” Dr. Narayanan says.

“If you look at prostate cancer, most of the time it occurs in patients over 40, and about 60% are over 60,” Dr. Miller says. “And it turns out that black men have a higher incidence, like 70% of the diagnoses, than white men.”

Existing treatments for prostate cancer target androgens, extending survival for most patients. However, roughly 30 percent of tumors do not respond, and patients who initially respond often develop resistance.

“Enzalutamide is normally the drug that’s chosen to give to men,” Dr. Miller explains. “And with time, it just doesn’t work. And we tried to figure out what’s going on there.”

One of the primary reasons for treatment failure or relapse is a mutation of the receptor protein for androgens. Enzalutamide works on one area of the receptor.

ONCT-534 is a dual-action androgen receptor inhibitor that has shown activity in prostate cancer models against unmutated and mutated androgen receptors. The research on the drug candidate has been funded by the National Cancer Institute, Oncternal, and GTx Inc., the company that became Oncternal.

“It looks like our drug is a very strong candidate for treating these patients who have relapsed from current treatment options,” Dr. Narayanan says. “It may potentially have the possibility to extend the survival.”

Dr. Narayanan and Dr. Miller are collaborators on several projects, including the preclinical development of a molecule to treat Kennedy’s Disease, a rare progressive neurodegenerative disease in younger men. Dr. Miller and his team are responsible for the chemistry, designing the molecules and testing and refining the structure. Dr. Narayanan and his team do the pharmacological testing to see how they perform in the lab.

Dr. Miller and Wei Li, PhD, UTHSC Distinguished Professor in the Department of Pharmaceutical Sciences and director of the UTHSC College of Pharmacy Drug Discovery Center, were collaborators in the initial design and testing of the drug sabizabulin, along with scientists at The Ohio State University and GTx Inc. Originally a cancer drug, sabizabulin’s anti-inflammatory capabilities were shown effective in treating acute respiratory distress from COVID-19. Veru currently holds the license to that drug through the UT Research Foundation and is working to get FDA approval.

Oncternal, the licensee for ONCT-534 has handled the lengthy process leading to FDA approval for clinical trials that will test safety, efficacy, and finally, how it compares against current standard treatments. Passing all three hurdles could advance a drug to market someday.

Drs. Narayanan and Miller are hopeful.

“I would say that would be my biggest success in my entire career,” Dr. Narayanan says. “It would be almost like my baby graduating and going out with flying colors.”