A previously unknown subtype of hormone-resistant prostate cancer accounts for about 30% of all cases, according to a new study by a team of scientists from Memorial Sloan Kettering Cancer Center (MSK) and Weill Cornell Medicine, published May 27, 2022, in the journal Science† The results could pave the way for targeted therapies for people with this subtype of prostate cancer.
Prior to this recent work, led by MSK physician scientist and Human Oncology and Pathogenesis Program member Yu Chen, only two subtypes of prostate cancer had been described: androgen-dependent and neuroendocrine. The team of dr. Chen calls the newly characterized third type stem cell-like (SCL), because some of the genes that are activated in the cells are reminiscent of those in stem cells.
To make their discovery, Dr. Chen and his team obtained 40 different patient-derived models of prostate cancer from people with cancer treated at MSK and Weill Cornell.
“We didn’t know if we would find any more subtypes,” says Dr. chen. “This is a field that has been studied by many researchers for years. So we were pleased and surprised to find that there is quite a large group of patients with tumors that have not been characterized.”
Innovative technologies enable new insights
One reason the subtype may have hinted to researchers is that there aren’t enough good lab models to study this type of cancer.
“Prostate cancer is extremely difficult to spread in the lab,” explains Dr. Chen out. “While there are hundreds of melanoma and lung cancer cell lines, there are only three or four prostate cancer cell lines that are useful.”
To get around this problem, the team turned to a new technology called organoids. The organ-like structures are grown in the lab from pieces of a patient’s tumor. They are a kind of ‘avatar’ of the patient’s tumor and can be used to study its genetics and biochemistry.
In addition, the team used patient-derived xenografts — tumors removed from a patient and grown in a mouse — for a total of 40 different patient-derived models of prostate cancer.
With these patient-derived organoids in hand, they can then determine which genes in the cells are turned on or off. This information was used by the scientists to determine that a new subtype of prostate cancer exists.
They then looked at whether the SCL subtype was visible in a biobank of 366 prostate cancer tumors. It was. In fact, it was the second most common group, after the androgen-sensitive type.
Knowing the molecular drivers of this common subtype of prostate cancer opens the door to approaches that could target these drivers with drugs.
New treatment options
“For the past 80 years, the backbone of prostate cancer treatment has been hormone deprivation therapy,” explains Dr. Chen out. “That’s because essentially all prostate cancers when they’re first diagnosed depend on testosterone signaling.”
“Once patients become resistant to antigen deprivation,” he continues, “it becomes a universally fatal disease.”
This is where the new findings could help improve treatment options. The scientists found that experimental drugs are currently being tested in humans that can block the growth of the SCL subtype in laboratory and animal models. They are currently working with several companies to set up a clinical trial of their drugs for people with this subtype of prostate cancer.
This research was supported by the National Institutes of Health (grants P30CA008748, P50CA221745, P50CA211024, R37CA241486, R37CA241486-02, U54CA224079, U01CA224044, R01CA193837, R01CA208100, U01CA252048, R01CA22821699, DP68201); the Department of Defense (W81XWH-17-1-0653), Prostate Cancer Foundation; STARR Cancer Consortium; Geoffrey Beene Cancer Research Center; Irma T. Hirschl Trust; and World Quant Foundation. dr. Chen has interests and receives royalties from ORIC Pharmaceuticals.
Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets
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dr. Chen has interests and receives royalties from ORIC Pharmaceuticals.
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