Two research teams converge on epigenetic switches that feed treatment-resistant metastatic prostate tumors. This research highlights the value of exploring gene regulation and large-scale structural changes in the cancer genome

More than three-quarters of metastatic prostate cancers that resist hormone-blocking therapies may harbor several duplicates of both the gene for a treatment resistance factor called the androgen receptor (AR) and of a never-before-seen genetic switch or enhancer, that boosts the gene's expression. The duplications, as well as epigenetic signs that the enhancer is active, appear after tumors are treated with AR-targeting drugs.

These genetic and epigenetic changes in the cancer cells coincide with a unique, widespread pattern of large-scale changes in tumor genome structure, which suggests a breakdown in molecular safeguards that normally keep a cell's genome stable.

These findings were published in concurrent papers in Cell by two separate research teams, each led by scientists from at the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute.

Looking beyond genes to the DNA that controls them

Advanced or metastatic prostate cancer is a sixth-leading cause of cancer death in the United States, claiming the lives of roughly 30,000 American men every year, according to statistics from the National Cancer Institute. Approximately three million men are living with prostate cancer in the US.

The AR protein is a receptor that provokes growth in advanced prostate tumors in response to two hormones, testosterone, and dihydrotestosterone. Researchers have studied the AR, the gene encoding it (called AR), and its signaling pathways for more than 20 years.

Much of the attention to date has focused on the development of therapies that either interfere with its function directly or that reduce the levels of AR-activating hormones in the blood referred to as androgen-deprivation therapies (ADT).

These two new studies highlight the need to explore regulators of AR, such as enhancers (stretches of non-coding DNA that serve as anchors for proteins that aid genes' expression) and other non-coding genomic or epigenetic elements. They also argue in favor of studying large-scale changes in genome structure that may influence AR activity, and how those changes may relate to the disease state.

"We've become very gene-centric in cancer research," said Broad associate member and Dana-Farber cancer geneticist Matthew Freedman, who was the senior author on one of the two Cell papers. "We tend to focus on questions like, 'What are the target genes of copy number gains and deletions?' I believe that as we begin to understand the non-coding genome better, we will see more and more examples of non-coding drivers in cancer."

"The first era of cancer genomics focused primarily on localized prostate cancer, and on coding genetic alterations in localized disease," said Srinivas Viswanathan, a research fellow in the Broad Institute Cancer Program, a prostate oncologist at Dana-Farber, and co-first author—with research fellows Gavin Ha of the Broad and Dana-Farber and Andreas Hoff of the Broad and Oslo University—on the other Cell paper.

"But what we see now is that there can be very significant genetic differences between disease states in prostate cancer, and that unique genetic changes—in both the coding and non-coding regions of the genome—can arise with advanced disease and in response to therapy."

Epigenetics brings a new enhancer to light

Using chromosome conformation analysis, Freedman, Takeda, and Spisák's team found that this non-coding region engages the AR gene promoter, further suggesting that it acts as an enhancer.

Also, they noted that they could curb AR protein production and cell growth in a metastatic prostate cancer cell line by suppressing the enhancer with the CRISPR-based genome and epigenome editing reagents. They also found that by adding a single additional copy of the enhancer to the cell line, they could confer increased resistance to enzalutamide, an anti-AR drug currently used for the treatment of ADT-resistant prostate cancer.

"The majority of advanced prostate cancers remain addicted to androgen receptor signaling as they transform and become treatment resistant," said Mary-Ellen Taplin, a prostate oncologist.

"These elegant studies demonstrate the previously unimagined complexity of alterations in the androgen receptor and provide promising new targets for therapy development."