It has been more than ten years since metastatic prostate cancer was first treated with medications like enzalutamide, which prevent male hormones from activating the androgen receptor. These medications can eventually stop working even if they are generally effective, although it is unclear why this happens.
According to a recent study from the University of Michigan Rogel Cancer Center, androgen receptor inhibitors have the potential to fundamentally alter the way prostate cancers behave, sometimes even making them more aggressive. These findings will be published in Nature Communications on Sept. 15.
The androgen receptor, which serves as the motor of prostate cancer cells, is activated by male hormones. The goal of treatment for people with advanced prostate cancer has been to interfere with these hormone levels for the past 80 years. This is commonly done with hormone-lowering injections and medications like enzalutamide.
Eventually, almost all cancers find ways to resist therapy and continue to grow with the help of male hormones in the majority of cases. The causes of additional cases of treatment resistance are still unclear.
“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 was interested in learning what was initially present in these tumors as well as what transpired when the tumors began to grow while being treated with 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.
Joshi Alumkal
He and his colleagues enrolled patients in a long-term trial to collect biopsies of metastatic tumors both before and after enzalutamide treatment. His team obtained repeated samples from 21 patients, which allowed them to comprehend the mechanisms at play in each patient’s tumor.
Alumkal says 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.”
The successive sampling approach used by Alumkal painted a considerably clearer picture of the potential development of enzalutamide resistance.
Most tumors revealed no appreciable changes in gene expression when they were compared to samples taken at baseline and during progression from the same patient.
“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.
Alumkal and his team saw a significant change in the wiring or gene expression program of the tumors in three of the 21 cases.
“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.”
Alumkal discovered that the tumors acquired fuel independence for a second reason in 15% of cases. These tumors showed a distinctive wiring pattern and were most consistent with the double-negative prostate cancer subtype, which no longer used the androgen receptor as an engine.
However, they did not develop into neuroendocrine prostate cancer either. Alumkal illustrates this trend using automobiles.
At first, almost all prostate cancers are like gas guzzlers; they are very dependent on fuel, and the androgen receptor serves as their engine. Most tumors remain fuel-dependent after hormone therapy, but they grow more fuel-efficient and can travel further on less fuel.
“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.
According to Alumkal, three tumors changed into double negative prostate cancer like 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 DNA mutations found in the baseline and progression biopsies from these converter tumors were the same, which strongly suggests that enzalutamide completely rewired the engine of the original fuel-dependent tumor to become fuel-independent at disease progression. It’s a dramatic shift to wrap your head around.”
Alumkal’s team discovered particular genes that were highly expressed in the baseline tumors that ultimately developed into double negative prostate cancer, despite the fact that the baseline tumors had a comparable appearance under the microscope.
This finding implies that some tumors exist in a hybrid condition, initially fuel-dependent but susceptible to developing into double-negative prostate cancers after enzalutamide therapy.
According to Alumkal, the sequential sampling method’s findings indicate that enzalutamide is forcing tumors to change, sometimes radically. Alumkal points out that the team still has work to do and that the gene signature he discovered is tentative.
“Still, the fact that the DNA looks similar in the converters strongly indicates that enzalutamide is reprogramming tumors. We have more work to do, but it may be possible up-front to identify patients at greatest risk of having their tumor become fuel-independent after treatment with drugs like enzalutamide,” he said.
