Multi-institutional study explores latest lifeline for advanced prostate patients

For men with advanced prostate cancer that not responds to traditional hormone therapies, treatment options are limited—and time is of the essence. Because the disease progresses, the window for effective, less intensive treatments begins to shut.

A multi-institutional clinical trial led by researchers on the Medical University of South Carolina (MUSC) and Emory University tested whether an experimental drug could extend the effectiveness of existing therapies. The study, published in , examined a novel strategy for overcoming treatment resistance in advanced prostate cancer.

This can be a very difficult population to treat. These are patients whose cancer has already develop into resistant to straightforward therapies, so there’s a transparent need for brand new options.”

Besim Ogretmen, PhD, study co-author and associate director, basic sciences, Hollings Cancer Center, Medical University of South Carolina

Attempting to increase the lifespan of existing therapies

The study focused on men with metastatic castration-resistant prostate cancer – an aggressive type of the disease that has spread and not responds to hormone-blocking treatments.

These treatments, namely the drugs abiraterone and enzalutamide, are standard therapies. They will be very effective initially, but most patients eventually develop resistance, so options are limited and sometimes require switching to chemotherapy, which may cause significant unintended effects.

“We’re all the time on the lookout for latest targets,” said Dr. Omer Kucuk, oncologist and Correll Chair in Genitourinary Cancer at Winship Cancer Center at Emory University, where he led patient recruitment and clinical efforts. “After androgen receptor therapies fail, there are limited precise options for individualized treatment.”

Reasonably than replacing these standard therapies, researchers tested whether a further oral medication could make them work higher, improve patient outcomes and extend the duration of response.

From MUSC discovery to clinical trial

The experimental drug at the middle of the study – opaganib – has its roots at MUSC.

Opaganib, a first-in-class therapy, was developed based on basic research led by Charles Smith, Ph.D., and advanced through years of laboratory and early-stage work at MUSC. This included an early clinical trial conducted at Hollings, which then progressed to a mid-stage clinical trial led by Hollings oncologist Michael Lilly, MD, now professor emeritus, that helped move the drug from early discovery to patient treatment.

“This is predicated on years of preclinical and early clinical studies,” Ogretmen said. “The goal was to take what we learned in our labs and see if we could improve patient outcomes.”

What is vital is that opaganib works in a different way than standard therapies. As an alternative of targeting hormones, it blocks a pathway involved in sphingolipid metabolism – a process cells use to administer lipids, or fats, that affect cell survival. Researchers are increasingly specializing in this pathway because disruptions in fat metabolism may also help cancers grow and develop into immune to treatment.

“There should not many drugs within the clinic that focus on this pathway,” Kucuk said. “That makes it very exciting and really different from the treatments we currently use.”

Early signals of effectiveness

On this phase 2 study, 66 patients received opaganib together with abiraterone or enzalutamide after their cancer had progressed.

About 15% of patients who took opaganib with abiraterone and 9% of patients who took it with enzalutamide achieved disease control after 16 weeks, falling in need of the study’s primary objective. Nonetheless, a better look revealed a more nuanced picture.

A subset of patients showed clear biological signs of response, including a decrease in prostate-specific values antigen (PSA) values ​​and phases of disease stabilization. These results suggest that the treatment may slow the disease and permit patients to proceed therapy for longer.

“Even when it is just a small percentage, these are real patients,” emphasized Ogretmen. “We’re talking about individuals who profit from this treatment while others didn’t work.”

Along with effectiveness, the tolerability of the medication can be a very important aspect. The mixture treatment was generally manageable, with most unintended effects being mild to moderate. Some patients experienced more serious unintended effects, but most improved when the medication dose was reduced or stopped.

A path to precision medicine

In accordance with the researchers, the outcomes represent a very important advance because they reveal a brand new biological technique to combat prostate cancer. A crucial next step will likely be identifying which patients are most probably to profit from the drug combination.

Using blood samples from the participants, the researchers now need to search for biomarkers or measurable signals within the blood that would predict a response. This approach could refine therapy for a smaller group of patients – an indicator of precision medicine.

“We are able to study what lipids change in patients who respond versus those that don’t,” Ogretmen said. “This may also help us stratify patients and higher match treatment to the best person.”

The study, supported partly by a National Cancer Institute (NCI) Program Project Grant to Ogretmen and the team, also highlights the facility of collaboration by bringing together teams from MUSC and Emory to maneuver a discovery from the laboratory to clinical testing.

“It was an important collaboration between the 2 institutions,” said Kucuk. “This can be a very novel approach and it was exciting to assist bring it right into a clinical setting.”

“The sort of work is determined by strong collaboration between academic researchers, clinicians and industry partners,” Ogretmen added. “In this fashion, we bring latest therapies to patients who otherwise don’t have any effective treatment options.”

Looking forward, researchers are confident that refining this approach or developing next-generation drugs that focus on the identical pathway could expand treatment options, with growing optimism that these therapies could develop into a part of future treatment strategies.