Researchers suggest how cancer treatment rewires the engine of prostate tumors


For more than a decade, drugs like enzalutamide, which block male hormones from activating the androgen receptor, have been used to treat metastatic prostate cancer. Although these treatments are generally effective, they may eventually stop working, but little is known about how this happens. A new study from the University of Michigan’s Rogel Cancer Center suggests that androgen receptor blockers can fundamentally rewire and reshape how prostate tumors work and, in some cases, even make them more aggressive. These results will be published in Nature Communications.

Male hormones work like fuel, activating the androgen receptor which acts as the motor for prostate cancer cells. For the past 80 years, treatment of advanced stage prostate cancer patients has focused on interfering with these hormone levels – now typically done through hormone-reducing injections and medications. such as enzalutamide. Eventually, almost all tumors develop workarounds and escape treatment, and in most cases tumors remain dependent on male hormones to fuel their growth. Other examples of treatment resistance remain poorly understood. “The greatest unmet need in the clinic right now is to understand workarounds for a tumor that becomes resistant to drugs that target androgen receptors so that we can determine how best to treat the patient whose tumor began to grow,” said Joshi Alumkal, MD, Wicha Family Professor of Oncology and Professor of Internal Medicine, whose team led this research in collaboration with the Zheng Xia Laboratory at Oregon Health & Sciences. University Knight Cancer Institute. Thomas Westbrook, MD, a hematology-oncology fellow, was the study’s co-first author with postdoctoral fellow Xiangnan Guan, Ph.D. “Once enzalutamide stops working, options are limited. 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 the tumors started growing on enzalutamide treatment. He and his colleagues recruited patients for a longitudinal study to obtain metastatic biopsies before enzalutamide treatment and when the tumor became resistant to treatment. His team collected serial biopsies from 21 patients, allowing them to understand each patient’s tumor workarounds.

Alumkal says this is the largest collection of matched metastatic biopsies before and after enzalutamide. “To understand drug resistance, researchers often take samples from some patients before treatment and from another group of patients whose tumors are resistant to treatment. However, this approach is much less precise because there could be d “other significant differences between these patients. You can’t tell if the differences have something to do with drug exposure or if they have more to do with the fact that the tumors are just different to start 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 changes in gene expression. “The fact that the gene expression program of a tumor before treatment appeared very similar to progression on enzalutamide is quite remarkable,” says Alumkal. “This shows how well most tumors were able to adapt and maintain the androgen receptor motor despite enzalutamide treatment.” But that wasn’t the only surprise.

In three of the 21 cases, Alumkal and his team found a profound change in the wiring – or gene expression program – of the tumors. “We knew that sometimes tumors become fuel-independent and no longer dependent on the androgen receptor. Instead, these tumors activate a more common gene expression program in nerve cells, rather than prostate cells, and turn into an aggressive form called neuroendocrine prostate cancer.”

But Alumkal found that in 15% of cases, the tumors also became fuel-independent for another reason. “These tumors were wired in a unique way and most closely matched a subtype of prostate cancer called double-negative prostate cancer, meaning the tumors no longer had the androgen receptor as their driver. But nor did they become neuroendocrine cancer of the prostate.” Alumkal uses vehicles to describe this change.

“Initially, almost all prostate tumors are energy-intensive: highly fuel-dependent and powered by the androgen receptor as a motor. When treated with hormone therapies, most tumors remain fuel-dependent but become more fuel-efficient in fuel, able to go further on less fuel.” Our work has shown that the majority of tumors – even after receiving enzalutamide – remain highly fuel-dependent, suggesting that continuing to target the receptor androgens could make a huge difference in these tumors,” Alumkal continued.

Alumkal found that three tumors turned into double-negative, electric vehicle-like prostate cancer. “The gasoline engine was replaced by a completely separate set of machines that allowed tumors to grow and survive,” Alumkal explained. The DNA mutations found in baseline and progression biopsies of these conversion tumors were the same, strongly suggesting that enzalutamide completely rewired the original fuel-dependent tumor motor to become fuel-independent. fuel during disease progression. “It’s a sea change to understand your head.” Although the baseline tumors looked similar under the microscope, Alumkal’s team identified specific genes that were highly expressed in those that eventually became double-negative prostate cancer. This result suggests that some tumors exist in a hybrid state, initially fuel-dependent but at risk of becoming fuel-independent double-negative prostate cancer during treatment with enzalutamide.

Alumkal says the results from the sequential sampling method suggest that enzalutamide causes tumors to adapt, in some cases dramatically. Alumkal notes that the genetic signature he identified is preliminary and the team still has work to do. “Nevertheless, the fact that DNA appears similar in converters strongly indicates that enzalutamide reprograms tumors. We still have work to do, but it may be possible to identify patients most at risk of seeing their tumor become fuel-independent after treatment with drugs like enzalutamide,” he said.(ANI)

(This story has not been edited by the Devdiscourse team and is auto-generated from a syndicated feed.)

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