Study Identifies Two Previously Unknown Subtypes of Prostate Cancer

Researchers in New York have identified a previously undiscovered subtype of hormone therapy-resistant prostate cancer as well as a set of molecules that drive its growth. The findings could lead to the development of therapies that treat this specific cancer.

An estimated 268,000 men will develop prostate cancer this year. Some tumors manage to resist treatment but still need testosterone and other hormones to grow. Castration-resistant prostate cancer arises when tumors evade treatment that deprives them of the hormones that drive their growth. In a study published recently in the journal Science, a joint team from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center used samples derived from patients to conduct a comprehensive survey of this cancer and the molecular changes that occur within these advanced malignancies.  

They found four subgroups of the cancer—two of which were not previously known. The team estimates that one of these two previously undiscovered types, which they call stem cell-like (SCL), accounts for approximately a quarter of castration-resistant prostate cancers. They also identified a set of proteins within SCL tumor cells that work together to fuel this treatment-resistant disease. Studies have shown that this same molecular pathway drives other solid tumors, including colorectal cancer and malignancies of the breast and lung, so efforts are already underway for treatments that could potentially interfere. 

“For patients that fall into this SCL group, we have found very promising drug targets, which future studies will work to validate,” says Dr. Ekta Khurana, WorldQuant Foundation Research Scholar and associate professor of physiology and biophysics at Weill Cornell Medicine.

Previously, scientists seeking to investigate castration-resistant prostate cancer have generally lacked enough cells derived from patients to capture its full diversity. For this study, however, the team had access to 40 tumor samples. Most of these came from a collection of organoids, which are tiny organ-like structures grown from tumor cells collected from patients at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center.

The researchers analyzed these cells’ DNA, RNA, and how compactly their DNA was packaged, a characteristic known as chromatin accessibility. Changes in this packaging contribute to cancer by altering genes’ availability for expression. The chromatin data led them to identify the four groups, including SCL and WNT, the other previously unidentified type of castration-resistant prostate cancers identified in the study.

To determine the proportion of cases they each may comprise, the researchers used RNA sequencing data to classify 100 patients from Weill Cornell Medicine and 266 from the organization Stand Up to Cancer. Depending on the set of patients, 22–30% fell into the SCL category, while WNT accounted for 5–7%. Focusing on SCL, they used sophisticated computational tools to integrate the molecular data and identify the malfunctioning pathway at the heart of this cancer. In SCL, proteins FOSL1, TEAD, YAP and TAZ become overly active and alter chromatin accessibility to propel tumor growth. In experiments, the researchers found that two molecules known to interfere with these proteins slowed the growth of the SCL cells, but not that of androgen-dependent cells—a result that highlights the potential for a targeted treatment.

“Once you can identify which type of tumor patients have, that’s very powerful information,” Dr. Khurana said.