Scientists Say This Vulnerability Can Be Attacked by a Targeted Drug Already in Clinical Trials to Treat Other Types of Cancers

An international team of researchers led by clinicians at Weill Cornell Medical College have discovered a genetic Achilles’ heel in an aggressive type of prostate cancer — a vulnerability they say can be attacked by a targeted drug that is already in clinical trials to treat other types of cancers.

In today’s issue of Cancer Discovery, the researchers report that the investigational drug had a dramatic response in animal models of neuroendocrine prostate cancer, and so provides the first hope of an effective human therapy for this lethal cancer.

While fewer than 2 percent of prostate tumors in men are initially classified as neuroendocrine, many common adenocarcinoma prostate cancers change their biology during hormone therapy and morph into this aggressive subtype.

The study is the largest in-depth analysis of neuroendocrine prostate cancer yet undertaken.

“The findings are very exciting, because our bench-to-bedside approach identified a new molecular target for a subtype of prostate cancer for which a drug is now available.” – Dr. Mark Rubin professor of pathology and laboratory medicine Weill Cornell Medical College

The finding is especially important because many men are now being treated with new, highly potent androgen suppression therapy, which these researchers believe will significantly increase the risk of future development of neuroendocrine tumors. Androgen is the fuel that feeds adenocarcinoma prostate cancers — the most common kind of prostate cancer — and androgen suppression therapy effectively destroys cancer cells that depend on this hormone.

Although most of the approximately 30,000 men who die of advanced prostate cancer each year had been treated with androgen suppression therapy, it is impossible to know how many of them developed neuroendocrine tumors because patients are not usually biopsied at that stage in their disease, the researchers say. Studies to define changing biology in prostate cancer are only now starting.

“Still, there is evidence to suggest that androgen suppression results in a more aggressive cancer in a growing number of men, and now, with this study, we may have a way to treat these patients.” – Dr. Himisha Beltran assistant professor Weill Cornell Medical College

The Weill Cornell researchers undertook the study to see if they could find a way to target neuroendocrine tumors, which is considered an orphan disease among other types of prostate cancer. They used a next-generation sequence analysis to study the transcriptome — the RNA messages that tumors produce — of neuroendocrine tumors compared to adenocarcinoma prostate cancers.

A series of analyses using prostate cancer samples gathered by researchers from the U.S. and Europe concluded that the majority of neuroendocrine prostate cancers significantly overexpressed AURKA and MYCN genes, and 40 percent of these tumors also had extra copies of these genes.

Surprisingly, they also found that a smaller subset of prostate adenocarcinomas also overexpressed these genes, and 5 percent had extra copies. “This may represent a high-risk population that could potentially benefit from screening and early intervention,” says Dr. Beltran.

In neuroendocrine prostate cancer, the AURKA and MYCN mutations need to work together to promote cancer development, Dr. Rubin says. The kind of lethal interaction has also been found in neuroblastoma, a pediatric brain cancer. But the very good news, he adds, is that aurora kinase inhibitors have been developed and are being tested in a variety of cancers.

This study demonstrated that the aurora kinase inhibitor PHA-739358 worked against human neuroendocrine prostate cells in the laboratory, and that it had a dramatic response in animal models of neuroendocrine prostate cancer. It shrank large tumors to very small sizes in a short period of time, compared to untreated mice. There was also significantly enhanced sensitivity of neuroendocrine prostate cancer compared to prostate adenocarcinoma, Dr. Rubin says.

“The Prostate Cancer Foundation was pleased to provide support for this research.” – Dr. Howard Soule chief science officer  Prostate Cancer Foundation