Achilles’ heel in deadly variety of prostate cancer raises hope of cure

Weill Cornell physician-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 an 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 two per cent of prostate tumours 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, and 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,” says the study’s senior investigator, Dr Mark A Rubin, a professor of pathology and laboratory medicine at 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 tumours.

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. But the treatment does not touch neuroendocrine cells that may have been part of the tumour mix, and those untreatable cells now have room to grow and spread, the researchers say.

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 tumours 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,” says the study’s lead investigator, Dr Hi­misha Beltran, assistant professor of medicine at Weill Cornell Medical College and a medical oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Centre.

The Weill Cornell researchers undertook the study to see if they could find a way to target neuroendocrine tumours, 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 tumours produce — of neuroendocrine tumours compared to adenocarcinoma prostate cancers.

A series of analyses using prostate cancer samples gathered by researchers from the US and Europe concluded that the majority of neuroendocrine prostate cancers significantly over-expressed AURKA and MYCN genes, and 40 per cent of these tumours also had extra copies of these genes.

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

Category: Health