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More than 70 years ago, a surgeon named Charles Brenton Huggins made a game-changing discovery about prostate cancer: in men who had the disease, tamping down levels of testosterone caused their cancer to regress.
Huggins and others soon confirmed that testosterone acts as a gas pedal for cancer growth in the prostate. At the time, there were no drug treatments for cancer because researchers simply didn’t believe that cancer cells could be chemically bullied out of the rampant growth that characterized them. Instead, the assumption was that cancer cells carried some sort of self-contained mechanism that made them divide willy-nilly. Huggins’s work showed for the very first time that cancers can also be driven by chemical or hormonal signals. The discovery earned him the Nobel Prize in 1966, and today, treating prostate cancer that has spread almost universally starts with testosterone deprivation.
Testosterone is an androgen, or male sex hormone, and although there are a handful of others, it’s the one that is present at the highest levels in men’s bodies, along with its close cousin, dihydrotestosterone (DHT). The prostate, a walnut-shaped gland that sits above the penis and produces a fluid that nourishes sperm, is something of a slave to androgens—it needs these hormones to develop properly and to function in adulthood. Androgens exert their power in the prostate by docking onto a special receptor called the androgen receptor (AR). When they do so, the receptor changes shape in a way that allows it to turn other genes on and off. With the AR as puppet master, this cascade of signals spurs prostate cells to divide and grow.
When this process goes awry and prostate cells turn cancerous, their androgen dependence continues, at least at first—and that’s why curbing androgen activity is at first such an effective treatment. Drug treatments that do this, often by blocking hormones’ interactions with the androgen receptor, are referred to as chemical or medical castration. In the past, before such drugs were available, surgical castration was used to the same end, but it is rarely used today.
The problem is that androgen deprivation therapy comes with a serious glitch: for virtually all men with prostate cancer, whether after decades or mere months of treatment, it eventually stops working. At that point, the cancer revs back up into progression mode, even though patients have little or no detectable testosterone coursing through their blood. For decades scientists were stumped about why prostate cancer develops resistance to this treatment and morphs into an androgen-independent form. But recent research is pointing to a culprit: a rogue version of the androgen receptor called AR-V7.
AR-V7 is what biologists call a “splice variant.” Although we generally think of genes as well-defined DNA sequences, each encoding a single protein, most genes actually encode a main version as well as several spin-off versions of a protein. The spin-offs are produced when the DNA-to-protein translation machinery skips around, passing over some segments of the gene. The resulting protein often works differently than the main version.
It turns out that something about androgen deprivation therapy causes the gene translation machinery to ramp up production of AR-V7, until it is as much as 20 times more prevalent than the normal androgen receptor protein. (Researchers don’t know specifically why, beyond the fact that cell processes are startlingly good at finding ways to barrel ahead with what they are programmed to do, even when some human intervention gets in the way.) In the case of AR-V7, the translation machinery skips one key segment, located at the end of the gene. This segment contains the binding site where androgens dock onto the receptor. That stretch acts as a switch that turns the receptor protein on or off. But when the switch isn’t there, the androgen receptor is locked in perpetual on-mode, driving cell growth and division without any brakes.
All of the androgen deprivation therapies—notably, including the two newest ones, abiraterone (Zytiga) and enzalutamide (Xtandi)—target the binding site. So it makes sense that they cease to work when a patient’s body becomes flooded with AR-V7, the stumpy version of the receptor that lacks the binding site. Indeed, prostate cancer patients who carry AR-V7 don’t seem to improve at all when they are given drugs that reduce androgen levels. Now that they understand why, clinicians and researchers believe that by testing patients for AR-V7 it may be possible to clearly predict which drugs will help them and which will do no good at all. Meanwhile, a phase 3 clinical trial currently underway is testing a compound called galeterone, which targets androgen receptors by degrading them entirely, not by blocking their binding site. In theory, AR-V7 would not be able to prevent such a therapy from working.
So far, tests for whether a patient’s tumor is producing AR-V7 are still experimental, but several research teams say they are hard at work trying to bring such a test to the clinic. Once it becomes available, a patient’s doctor would be able to tell in minutes whether he should continue with androgen deprivation drugs or instead try a completely different approach, such as chemotherapy or immunotherapy. Even when AR-V7 testing does become widely available, it will be just one component in a patient’s discussion with his doctor about the most appropriate treatment for him.