Researchers uncover how deadly prostate cancers are programmed to resist treatment

A clinical trial at OHSU and UC San Francisco points the way to potential targeted therapies.

The drug enzalutamide is a mainstay of treatment for men with life-threatening prostate cancer that has spread to other organs and can’t be stopped by older drugs. But enzalutamide does not work in about one-third of patients, for reasons that have remained largely unknown. That is, until now.

A new study conducted at OHSU and the University of California San Francisco has revealed a resistance program in the gene activity of tumor cells in men who don’t respond to enzalutamide. The findings point the way to potential new treatments that target the signaling pathways active in resistant tumors.

Image: color-enhanced, microscope view of prostate cancer cells (Annie Cavanagh/Wellcome Collection)

“Our clinical trial provides new clues about why enzalutamide may not work well to control certain prostate cancers and provides a new roadmap to test drugs that we would not have otherwise thought to be relevant,” first author Joshi Alumkal, M.D., said in a news release.

“Ultimately, we hope to identify drugs that can block this resistance program so we may develop new clinical trials that focus on patients whose tumors are inherently resistant to treatment with enzalutamide and drugs like it.” Alumkal heads the prostate and genitourinary medical oncology section at the University of Michigan Rogel Cancer Center. He led the research while he was at the OHSU Knight Cancer Institute.

The research emerged from a Prostate Cancer Dream Team grant from Stand Up To Cancer, the Prostate Cancer Foundation and the American Association for Cancer Research, which brought six centers together. “The collaboration made it possible to quickly accrue enough patients. It also brought together the pathology, laboratory and computational skills needed to conduct this kind of research,” said Tom Beer, M.D., deputy director of the Knight Cancer Institute, principal investigator for the Dream Team at OHSU, and co-author of the new study to be published this week in the journal PNAS.

Tom Beer, M.D.

The researchers enrolled 36 men with metastatic prostate cancer that was resistant to androgen deprivation therapy, a standard treatment that lowers the level of androgen hormones that drive the growth of prostate cancer. They were treated with the drug enzalutamide, which blocks signals from androgen by occupying the sites, called receptors, on prostate cancer cells where the hormone could bind.

Cancers in 25 men responded to enzalutamide, as measured by a decline in prostate specific antigen of 50 percent or more after 12 weeks. Cancers in 9 men did not respond to the drug. (In two cases, the researchers weren’t able to measure PSA level at 12 weeks).

Biopsies of metastatic tumors yielded enough DNA for gene sequencing of 26 cases, and RNA sequencing in 25. Computational biologists on the research team analyzed gene activity and they used a method called gene set enrichment analysis (GSEA) to identify patterns that correlated with enzalutamide resistance.

They found no substantial differences in androgen receptor gene expression or gene sequence alterations between those that responded to the drug and those that did not. But in tumors from patients with enzalutamide resistance, they identified several sets of genes that were activated – including genes linked to low androgen receptor activity and genes associated with “stemness” – a more primitive state of development that’s more resilient and adaptable.

“Patients who had more resistant disease appear to have a more stem-cell like variant of prostate cancer that does not have as much androgen receptor activity,” Beer said. “That makes clear that we need to extend our research focus beyond the androgen receptor.”

Alumkal said his team plans to focus on testing drugs with the potential to block the newly identified stemness pathways using laboratory models that accurately reflect the biology of human tumors that do not respond to enzalutamide.

At OHSU, Beer said his team is applying a similar approach to understand immune therapies for prostate cancer and find ways to predict response. The team is also pursuing clinical trials using the Knight Cancer Institute’s SMMART platform, in which repeated analyses of each patient’s cancer over time makes it possible to adjust targeted drugs to try to stay ahead of cancer’s ability to evolve.

“This is why we are doing more and more biopsies for metastatic patients in the clinic, to understand their individual cancers,” Beer said. “Cancers are distinct and we’re moving to a more precision approach. Instead of one size fits all, we need one size fits one.”

Further reading:

Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance by Joshi J. Alumkal, Duanchen Sun, Eric Lu, Tomasz M. Beer, George V. Thomas, Emile Latour, Rahul Aggarwal, Jeremy Cetnar, Charles J. Ryan, Shaadi Tabatabaei, Shawna Bailey, Claire B. Turina, David A. Quigley, Xiangnan Guan, Adam Foye, Jack F. Youngren, Joshua Urrutia, Jiaoti Huang, Alana S. Weinstein, Verena Friedl, Matthew Rettig, Robert E. Reiter, Daniel E. Spratt, Martin Gleave, Christopher P. Evans, Joshua M. Stuart, Yiyi Chen, Felix Y. Feng, Eric J. Small, Owen Wittes, and Zheng Xia. PNAS (2020)

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