A Cleveland Clinic-led research team has discovered that a metabolite of an agent approved for use against metastatic prostate cancer may be more effective than the parent drug, abiraterone. Known as Δ4-abiraterone (D4A), this novel metabolite shows more potent anti-tumor activity than abiraterone in some patients.
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Results of the investigation by Cleveland Clinic researcher Nima Sharifi, MD, and colleagues were published online in Nature in June.
“More studies are needed to uncover the exact mechanisms involved, but we predict that direct treatment with D4A could prolong survival in some patients with metastatic prostate cancer,” says Dr. Sharifi. “Further studies will also help us develop a potential biomarker profile to predict which patients will respond to abiraterone, which is converted to D4A.”
The major significance of the finding regarding abiraterone, says Dr. Sharifi, “is that in addition to its known direct effect, it has this very much indirect effect, meaning it’s converted to a totally different entity that has its own anti-tumor activities. So when you put them all together, it essentially makes it more potent than the parent compound. The way this is being metabolized is very different from the way we traditionally think of drug metabolism,” he says.
Prostate cancer is the most common malignancy in men, with about 240,000 new cases diagnosed every year in the United States. Nearly all fatal cases involve castration-resistant tumors, so much research focuses on finding effective treatment for these advanced cancers.
Mechanism of action of abiraterone
Prostate cancers need androgens in order to grow, so all metastatic prostate cancers require medical or surgical treatment to block testosterone production. Androgen deprivation, or medical castration, slows the spread of aggressive prostate cancer, with between 80 and 90 percent of tumors responding initially. However, almost all tumors eventually become resistant to hormone deprivation (i.e., castration-resistant), so it is a temporarily effective treatment, Dr. Sharifi says.
Castration-resistant prostate cancers continue to grow because testosterone production may still occur in the adrenal glands and in the tumor itself.
In previous research, Dr. Sharifi described a genetic mutation that allows prostate cancer cells to produce androgens, thereby providing their own fuel. This hyperactivated enzyme, he explains, “converts precursor steroids to the most potent androgens, and those androgens are responsible for driving disease progression in the setting of castration-resistant prostate cancer.”
Regardless of the mechanism of continued growth, however, castration-resistant tumors require alternative therapies.
Abiraterone is an inhibitor of androgen biosynthesis. The U.S. Food and Drug Administration approved its use in 2011 for men with metastatic castration-resistant prostate cancer who had undergone previous chemotherapy including docetaxel. In 2012, the FDA approved abiraterone’s use in combination with prednisone among patients without previous chemotherapy.
Abiraterone works by inhibiting cytochrome P45017A1 (CYP17A1), an enzyme needed for androgen synthesis. The specific action of abiraterone is to block enzymatic reactions that allow the conversion of precursor steroids to 5α-dihydrotestosterone (DHT). Tumors require DHT for resistance, so blocking its synthesis improves survival.
Conversion to efficacious metabolite
In the abiraterone study, conducted at Cleveland Clinic’s Lerner Research Institute, Dr. Sharifi and his collaborators showed that abiraterone undergoes conversion to the metabolite D4A in both humans and animal models of prostate cancer. The metabolite was found to inhibit three enzymes essential for DHT synthesis, namely 3β-hydroxysteroid dehydrogenase, steroid-5α-reductase, and 17β-hydroxysteroid dehydrogenase. D4A also blocked the androgen receptor directly with a higher affinity than did abiraterone, and inhibited androgen-responsive genes.
The degree of conversion of abiraterone to D4A varies among patients. “We think it’s possible that the amount of conversion to the metabolite may be in part responsible for either tumor response to the drug or resistance to the drug,” Dr. Sharifi says. This means that patients with a higher level of conversion may have better tumor response.
In fact, says Dr. Sharifi, “If a patient is on abiraterone, we can draw blood, look for the parent compound as well as the metabolite, and the degree of conversion could be an early biomarker of how well that drug might work.”
The metabolite study also showed that D4A has better anti-tumor activity than does abiraterone. Experiments in mouse xenografts showed that inhibition of steroidogenesis and tumor growth was significantly better with D4A than with abiraterone.
Not only do the findings on D4A help explain the efficacy of abiraterone, but they imply that direct treatment with D4A may achieve better clinical efficacy. “Because D4A is more potent, directly giving this metabolite may have better overall effects, meaning anti-tumor clinical effects, compared with giving the parent compound itself,” Dr. Sharifi says.
Studying future implications
Dr. Sharifi and his colleagues are pursuing new leads raised by their findings. “We’re in the process of looking at patients who get abiraterone and either respond with longer survival or longer progression-free survival versus those who don’t, to determine if that might correlate with conversion to D4A,” he says.
His work on D4A may have broader implications for other prostate cancer therapies as well. “This may tell us something about how drugs in this class work,” says Dr. Sharifi. “There are other drugs that are being investigated in clinical trials whose steroidal structure is similar to abiraterone’s, so figuring out how they work – the direct mechanism and the indirect mechanism through metabolites – may help us more appropriately develop these agents.”
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