Can a Genetic Signature Predict Which Prostate Cancers Spread?

By Cari Wade Gervin
Monday, January 25, 2021
Specialty: 

A new study could lead to better tailoring of treatments to individual patients.

It may be possible to determine which localized prostate cancers will metastasize, even when caught very early on, according to a recent study published in Nature Cancer.

“We identified a 16-gene signature that is enriched in bone metastasis, and that can predict whether localized tumors would metastasize early, as well as whether metastases are less likely to respond to current standard-of-care treatments,” says lead author Juan Arriaga, PhD, a postdoctoral research scientist at Columbia University Vagelos College of Physicians and Surgeons and the school’s Abate-Shen Lab.

The research, while still in early stages, could have a significant impact on prostate cancer treatment.

Why It Matters

One in eight men will get prostate cancer in his lifetime, according to the American Cancer Society. Fortunately, due to advances in chemotherapy, radiation and immunotherapy, the five-year relative survival rate for localized prostate cancer is close to 100%.

But for men who have cancers that do metastasize to distant parts of the body, 70% are likely to die within five years. In fact, prostate cancer is the second leading cancer-related cause of death in men and kills more than 33,000 people in the U.S. every year.

“If we could know in advance which patients will develop metastases, we could start treatments earlier and treat the cancer more aggressively,” says Cory Abate-Shen, PhD, the study’s senior author and Chair of the Department of Molecular Pharmacology and Therapeutics, the Michael and Stella Chernow Professor of Urologic Sciences, and professor of pathology and cell biology at Columbia University Vagelos College of Physicians and Surgeons.

“The problem is that with existing tests, it’s hard to know which cancers are which,” adds Arriaga. “We miss a lot of aggressive cancers that should have been treated earlier, and we overtreat some slow-growing cancers that probably would not have spread.”

“By identifying genes enriched in bone metastasis, we can begin to understand what are the molecular processes responsible for bone metastasis, and therefore how to design better therapies to prevent their occurrence or treat them once they occur.”
— Juan Arriaga, PhD, postdoctoral research scientist at Columbia University Vagelos College of Physicians and Surgeons and the school’s Abate-Shen Lab

From Mice to Men

Arriaga and his team at the Abate-Shen Lab started with mice, developing a unique model in which the cancer spontaneously metastasizes to bone in the research animals.

“This allowed controlled and comprehensive studies of bone metastasis that had not been possible before,” Arriaga says. “These studies showed bone metastases from these mice were molecularly conserved with human cancer.”

The researchers found that bone metastases have a different molecular profile than that of primary tumor, including specific patterns of subclonal branching, and that variations in the MYC and RAS genes, along with 14 others, can activate metastases in prostate cancer in mice. After testing the now-called META-16 gene signature in human samples, they found it reliably predicted which patients had cancer that would metastasize— and how long that cancer would take to metastasize. It also predicted which patients’ cancers would respond to anti-androgen therapy, a therapy used to suppress the hormone that often encourages tumor growth.

“By identifying genes enriched in bone metastasis, we can begin to understand what are the molecular processes responsible for bone metastasis, and therefore how to design better therapies to prevent their occurrence or treat them once they occur,” Arriaga says.

How the Research Can Help Treatment

Recent innovations in cancer treatment have brought striking improvements in the treatment of metastatic prostate cancer. Anti-androgen therapy in particular can benefit a certain subset of patients, but it’s not always easy to determine who those patients are.

“One current challenge in patients with localized prostate cancer is deciding whether to administer certain treatments or not,” Arriaga says. “These treatments may have considerable side effects, so we want to treat only the subset of patients that will likely benefit, while sparing the rest from unnecessary side effects.”

If further research bears out what the team has learned so far, it could help identify which patients are more likely to respond to a particular therapy and allow better tailoring of treatments to individual patients, an approach that researchers hope will improve overall outcomes. As Arriaga says, “Our gene signature now provides a new tool that can be used to guide precision medicine for … androgen receptor signaling inhibitors.”

What’s Next

Further clinical trials are planned, although the pandemic has slightly slowed things down.

“The next step is to design trials that could tell us whether the use of our signature can actually be of use to clinicians and bring benefits to patients,” Arriaga says. “We hope our studies can help reduce mortality rates and spur the development of novel therapies.”

The team also is interested in finding out whether this type of sequencing might be replicable for other types of metastatic cancer and could thus could hold multifold treatment potential.

“As other cancers metastasize to bone, it would be very interesting to study whether our signature can be applied in such contexts as well,” Arriaga says.