When Hormones Stop Working: New Receptors May Explain Why

The most confounding aspect of hormonal therapy for prostate cancer — depriving the prostate of testosterone and other androgens (male hormones), that nurture it — is that at first it works very well; in fact, it can keep working for many years. But eventually, in most patients it stops working, and the cancer becomes what doctors call “hormone-refractory.” The cancer, continually evolving
and worsening, somehow develops the ability to survive even in the absence of hormones, and when it reaches this point, cancer is at its deadliest.

This is the last-ditch stage of metastatic cancer, and Jun Luo, Ph.D., the Phyllis and Brian L. Harvey Scholar, may have found a crack in its armor — newly discovered androgen receptors. Hormones work in the body as chemical signals, which act as keys for highly specific locks, called receptors. “In order to function properly,” says Luo, “androgens entering the prostate cancer cells need to find and tag the androgen receptor. The tagged androgen receptor then migrates to the cell nucleus, and activates an army of genes that support the growth of prostate cancer.” This is called the androgenic signaling pathway, and “despite decades of effort, there is still much to explore before we will fully understand how this pathway works in hormone-refractory prostate cancer.”

Luo and colleagues discovered sneaky new forms of androgen receptors that somehow
manage to keep this pathway going — even without hormones — and relay the androgenic signals without being tagged by androgens. Like stealth planes, they don’t get picked up on the radar. “These new androgen receptors, unlike the androgen receptors previously known to us, can support prostate cancer growth in the complete absence of androgens,’’ says Luo. “This discovery may help to explain how prostate cancer cells escape hormone treatment and become hormone-refractory.”

In normal prostate tissue, Luo and colleagues found, these new receptors are present at low levels. But in hormone-refractory cancer cells, they are “increased by twenty-fold.” The next step, he says, “is to design specific inhibitors for these new androgen receptors, to see whether this will help block the progression to hormone-refractory prostate cancer.” The scientists also hope to develop biomarkers “that may help to monitor the effectiveness of treatment, and also help determine which patients are more likely to benefit from hormone therapy.”

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