One of the most challenging aspects of treating advanced prostate cancer is that – because each case of prostate cancer is unique – not every drug is effective in every man. Enzalutamide is a prime example: Approved in 2012 by the Food and Drug Administration for certain men with advanced prostate cancer, it targets the androgen receptor. "Even when prostate cancers reach very advanced stages, they remain responsive to interventions that either suppress androgen production or block the androgen receptor," says scientist Jun Luo, Ph.D. "However, not all patients benefit from this drug." In fact, an estimated 20 percent to as many as half of men who are eligible to take this drug show no response to it.
Not every drug is effective in every man.
So how does a man know, without having to take enzalutamide for weeks or months, if he’s in the group who could be helped by it? Luo and oncologist Emmanuel Antonarakis, M.D., have been working to develop a blood test that can spare men the trouble and expense of taking a drug that won’t fight their cancer. The key, they believe, is a faulty androgen receptor (AR) molecule called AR-V7, which was discovered in Luo’s laboratory in 2008. "It is an abnormal version of the androgen receptor," says Luo, "and it’s missing the part of the AR molecule to which enzalutamide binds." In men with AR-V7, the drug acts like a key that doesn’t fit the right lock – it doesn’t connect. "The androgen receptor axis remains active even when the normal receptor is blocked by enzalutamide," Luo explains, and men with this aberrant molecule do not respond to the drug.
It has not been easy to translate this idea from the laboratory into the clinic. First, Antonarakis and Luo worked together to see whether AR-V7 could be detected in blood samples by examining circulating tumor cells in men with advanced prostate cancer. They found that it could. The next major hurdle has been to find out whether the presence of AR-V7 foretells the treatment response to enzalutamide. "Our hypothesis is that men who have a normal AR molecule will respond favorably to enzalutamide, while men who harbor the AR-V7 molecule will demonstrate resistance to the drug."
If their theory is proven correct, it will not only offer men a simple blood test that will help guide their treatment; this work also points to a direction for drug development – "the discovery of new drugs that also target the AR-V7 molecule," says Luo, "of which there currently are none."