A newly identified, previously unknown subtype of hormone-resistant prostate cancer accounts for about 30% of all cases, according to a new study in Science from a team of scientists at Memorial Sloan Kettering Cancer Center (MSK) and Weill Cornell Medicine. The results could pave the way for targeted therapies for people with this subtype of prostate cancer.
Prior to this recent work, which was led by MSK researcher Yu Chen, MD, PhD only two prostate cancer subtypes had been described: androgen dependent (requiring testosterone) and neuroendocrine. Chen’s team calls the newly characterized third type stem cell-like (SCL), because some of the genes that are turned on in the cells are reminiscent of those in stem cells.
Through the process of lineage plasticity, prostate cancer cells can switch their lineage program away from the prostate lineage by using different transcriptional master regulators, Chen explained.
“We wanted to study the gene expression patterns in hormone-resistant prostate cancers and use a bioinformatics approach of looking at open chromatin, which is where transcription factors master regulators land,” says Chen. “The idea was to identify the master regulator transcription factors for these different gene expression patterns and learn more about the different patterns of prostate cancer subtypes.”
His team examined a large human biobank of patient tumors of 366 prostate cancer tumors. They discovered four patterns of hormone-resistant prostate cancers, including two new subtypes. The first and most common, accounting for 50% to 60% of all, retained its prostate lineage by reactivating the testosterone receptor despite castration therapy. They also saw the neuroendocrine subtype, representing 10% of cases.
“And then we found this new subtype, which to a pathologist still looks kind of prostate-like,” Chen said, acknowledging that it would seem reasonable to try different hormonal therapies with these tumor. “But we found that these cancers, which we call stem cell-like, no longer are dependent on the testosterone receptor but switch to other transcription factors.”
The team observed that this SCL subtype is the second most common, accounting for about 30% of these cancers. The researchers also observed a rare fourth subtype, representing 2%-3% of patients.
“This information tells us that further hormonal therapy will be inactive or minimally active in patients with the SCL subtype,” says Chen.
Additional chromatic immunoprecipitation sequence revealed some of the master regulators involved in SCL hormone-resistant prostate cancer.
“The target is actually two sets of transcription factors,” Chen explained. The first is AP-1 working together with the combination of YAP, TAZ, and TEAD proteins. TEDE is a transcription factor; YAP and TAZ are transcriptional coactivators for TEDE. “This means that YAP/TAZ and AP-1 represent potentially important clinical targets for people with this kind of hormone-resistant prostate cancer,” he says.
Using preclinical drugs against these targets, the team found that they block the growth of the SCL subtype in laboratory and animal models. They are working with drug manufacturers to find suitable drug candidates to evaluate in human clinical trials.
