Research suggests commonly used prostate cancer treatment rewires engine of prostate tumors: Biopsies from the same patients before and after treatment reveal how a specific drug reprograms prostate tumors

Drugs like enzalutamide that inhibit male hormones from activating the androgen receptor have been used to treat advanced prostate cancer for more than a decade. While successful in most cases, these drugs can eventually stop working, but there is a limited understanding about how this change occurs.

A new study from the University of Michigan Rogel Cancer Center suggests androgen receptor inhibitors can fundamentally rewire and reshape how prostate tumors function, and in certain cases even make them more aggressive. These findings will be published in Nature Communications on Sept. 15.

Male hormones function as fuel, turning on the androgen receptor that acts as the engine of prostate cancer cells. For the past 80 years, treatment for patients with advanced prostate cancer has focused on interfering with these hormone levels — now typically done through hormone lowering shots and drugs like enzalutamide. Eventually, nearly all tumors develop workarounds and escape treatment, and in most cases, tumors remain dependent on male hormones to power their growth. Other examples of treatment resistance remain poorly understood.

“The greatest unmet need in the clinic right now is understanding the workarounds in a tumor that becomes resistant to androgen receptor targeting drugs so we can determine how best to treat the patient whose tumor has begun to grow,” said Joshi Alumkal, M.D., Wicha Family Professor of Oncology and Professor of Internal Medicine, whose team led this research in collaboration with the Zheng Xia laboratory at the Oregon Health & Sciences University Knight Cancer Institute. Thomas Westbrook, M.D., hematology-oncology fellow, was the study’s co-first author along with post-doctoral fellow Xiangnan Guan, Ph.D. “Once enzalutamide stops working, there are limited options. We don’t know how or why most tumors become resistant.”

Alumkal wanted to understand what was present in these tumors to begin with and what happened after tumors started to grow on enzalutamide treatment.

He and colleagues recruited patients to a longitudinal study to obtain metastatic biopsies before enzalutamide treatment and at the time the tumor became resistant to treatment. His team collected serial biopsies from 21 patients, enabling them to understand the workarounds in the tumor from each patient.

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