Biopsies from the same patients before and after treatment reveal how a particular drug reprograms prostate cancer tumors.
For more than a decade, drugs such as enzalutamide (also known by the brand name Xtandi) that block male hormones from activating androgen receptors have been used to treat advanced prostate cancer. Although these medications are successful in most cases, sometimes they eventually stop working. However, there is limited understanding of how this change occurred.
A new study suggests that androgen receptor inhibitors can essentially rewire and reshape how prostate tumors function. In fact, in some cases, they can even make tumors more aggressive. These results from Rogel Cancer Center at the University of Michigan To be published today (September 15, 2022) in the magazine Eventually, nearly all tumors develop workarounds and escape treatment. In most of these 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. He is the Wicha Family Professor of Oncology and Professor of Internal Medicine, and his 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 was interested in learning what was present in these tumors to begin with and understanding what happened after tumors started to grow on enzalutamide treatment.
He and colleagues recruited patients for a longitudinal study to obtain metastatic biopsies before enzalutamide treatment and at the time the tumor became resistant to treatment. Serial biopsies from 21 patients were collected by his team, enabling them to understand the workarounds in the tumor from each patient.
According to Alumkal, this is the largest collection of matched metastatic biopsies before and after enzalutamide. “To understand resistance to drugs, researchers often collect samples from some patients before treatment and from a different group of patients whose tumors are treatment resistant. However, that approach is much less precise because there could be other significant differences between those patients. You can’t pinpoint if the differences have anything to do with drug exposure or have more to do with the tumors just being different to begin with.”
Alumkal’s sequential sampling method provided a much clearer picture of how enzalutamide resistance might emerge.
When they compared the baseline sample to the progression sample from the same patient, most tumors showed no significant gene expression changes. “That the gene expression program of a tumor prior to treatment looked very similar at progression while on enzalutamide is quite remarkable,” Alumkal says. “It speaks to how well most of the tumors were able to adapt and keep the androgen receptor engine on despite enzalutamide treatment.”
But that wasn’t the only surprise.
In three of the 21 cases, Alumkal and his team saw a profound shift in the wiring—or gene expression program—of the tumors.
“We knew that sometimes tumors become fuel-independent and no longer rely on the androgen receptor. These tumors instead turn on a gene expression program more common in nerve cells, rather than prostate cells, and shift to an aggressive form called neuroendocrine prostate cancer.”
However, Alumkal found that in 15 percent of cases, the tumors also became fuel-independent for another reason. “These tumors were wired in a unique way and were most consistent with a subtype of prostate cancer called double-negative prostate cancer, meaning the tumors no longer had the androgen receptor as an engine. But they also did not become neuroendocrine prostate cancer.”
Alumkal uses vehicles to describe this change.
“Initially, nearly all prostate tumors are gas guzzlers: very fuel dependent and powered by the androgen receptor as the engine. When treated with hormonal treatments, most tumors remain fuel-dependent but become more fuel efficient, able to go farther with less gasoline.
“Our work showed that the majority of the tumors—even after receiving enzalutamide—remain very fuel-dependent, which suggests that continuing to target the androgen receptor could make an enormous difference in these tumors,” Alumkal continued.
Alumkal found that three tumors converted to become double negative prostate cancer—akin to an electric vehicle. “The gasoline engine was replaced by a completely distinct set of machinery that allowed tumors to grow and survive,” Alumkal explained. The
Reference: “Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity” 15 September 2022, Nature Communications.
Funding: Stand Up To Cancer, Prostate Cancer Foundation, NIH/National Cancer Institute, NIH/National Cancer Institute, NIH/National Cancer Institute, NIH/National Cancer Institute, NIH/National Cancer Institute, NIH/National Cancer Institute, NIH/National Cancer Institute, NIH/National Cancer Institute, U.S. Department of Defense, U.S. Department of Defense, Doris Duke Charitable Foundation, The V Foundation, National Comprehensive Cancer Network, Astellas Pharma, The Sheppard Family Fund, University of Michigan Rogel Cancer Center