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AR Mutations as a Predictor of Therapeutic Response

If hormonal therapy — blocking testosterone, also called “androgen deprivation therapy” — stops working in a man with metastatic prostate cancer, the next step is to go after the androgen receptor (AR). If testosterone is the key, then the androgen receptor is the lock it fits; sometimes, disabling the lock gives an extra benefit for these men. There’s a problem, however: “Some men become resistant to AR-targeting drugs,” says scientist Paula Hurley, Ph.D. It may be that these drugs don’t work because the androgen receptor defies the attempt to block it and keeps on functioning, “possibly through amplification or mutation of the AR gene.” In our last issue, Discovery reported on a test for a variant AR gene, called AR-V7, developed by Jun Luo and Emmanuel Antonarakis. For men who have this variant, the drugs enzalutamide and abiraterone do not work well.

If testosterone is the key, then the androgen receptor is the lock it fits; sometimes, disabling the lock gives an extra benefit.

“These types of AR gene alterations are almost exclusively seen in patients treated with therapies blocking androgen-AR activity,” Hurley notes. “However, there is still a lot we don’t understand about these AR mutations. Confounding variables have hindered our ability to determine fully their predictive capability and biologic role. For example, the prevalence of each individual AR mutation remains low. But AR mutations often overlap, making it difficult to determine their individual contribution to resistance.”

We need a better understanding what these different mutations do, and how they interact, says Hurley. With support from the Patrick C. Walsh Prostate Cancer Research Fund, she will explore how these AR mutations affect a man’s response to anti-cancer drugs, with the hope of finding ways around these roadblocks — so the medicines can work better in the men who need them most.

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