Clues to side effect may prolong prostate cancer survival

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Scientists believe they’ve figured out why a common drug for late-stage prostate cancer often loses effectiveness and can even make things worse.

The drug, enzalutamide, stops working after four or five months and appears to have a dual function that later turns the cancer into a relentless aggressor.

The new research indicates how to block the harmful side effects of the drug, at least in mice.

“As more patients look to enzalutamide to extend their lives, even for just a few months, our goal is to find ways to make the drug work for longer periods and to block the dangerous pathways that lead to adverse side effects,” says Chawnshang Chang, professor of pathology, urology and radiation oncology at the Wilmot Cancer Institute at the University of Rochester, and corresponding author of the paper in Nature Communications.

Prostate cancer is the second leading cause of cancer death in American men. Although doctors can treat some early-stage types with a “watch and wait” approach, other types are higher-grade cancers that require surgery and androgen deprivation therapy (ADT).

The goal of this treatment is to lower the amount of male sex hormones (androgens), which fuel the cancer. An especially aggressive subtype of the disease—castration-resistant prostate cancer—keeps growing despite treatment.

For men who have this aggressive form of metastatic prostate cancer and are no longer responding to chemotherapy, enzalutamide can extend survival by an average of five months. In 2018 the Food and Drug Administration also approved the drug to treat men who have castrate-resistant prostate cancer that hasn’t spread.

But enzalutamide can cause side effects, most notably, neuroendocrine differentiation (NED), an increase of neuroendocrine cells in the prostate tumors. An abundance of these cells makes tumors resistant to treatment.

Researchers identified non-coding RNA-p21 as the main culprit for inducing neuroendocrine differentiation, saying that IncRNAp-21 can switch the function of a key gene, EZH2. They also showed that IncRNAp-21 is highly expressed in NED prostate tumors.

Earlier, scientists believed that only a tiny percentage of advanced prostate cancer tumors underwent neuroendocrine differentiation.

But recent studies estimate that 30 to 40 percent of patients have tumors containing aggressive neuroendocrine prostate cancer cells for which the average survival rate after detection is less than one year—making more patients vulnerable to the worst-case disease progression, Chang says.

The latest discovery has the potential to affect men with challenging cases, says Edward Messing, an authority in urologic cancers who treats patients at the University of Rochester Medical Center.

“Dr. Chang’s team has identified an important molecular mechanism that affects many of the thousands of men with advanced prostate cancer who will eventually succumb to their disease. Understanding and reversing the ‘switch’ that causes neuroendocrine differentiation should prolong the lives of these men and significantly reduce their suffering.”

Although no treatments are available yet in clinical trials to block to molecular switch, Chang’s lab identified a small molecule drug that appears to work in mice, but the development needs further study.

The National Institutes of Health and the Taiwan Department of Health Clinical Trial and Research Center of Excellence funded the investigation.

Source: University of Rochester