Israeli-led researchers have identified a previously underappreciated mechanism that may explain why many prostate cancers stop responding to standard hormone therapy, potentially opening the door to new treatment strategies.
The study, led by Prof. Yosef Yarden of the Weizmann Institute of Science, focuses on a genetic alteration known as a gene fusion, in which two separate genes abnormally join to form a single hybrid gene. The mutation is found in about half of all prostate cancer cases.
Prostate cancer is one of the most commonly diagnosed cancers among men worldwide, with approximately 1.4 million new cases recorded annually. Treatment typically involves reducing or blocking male hormones such as testosterone, often in combination with surgery, radiation or chemotherapy, depending on the stage of the disease.
While hormone therapy is often initially effective, many tumors eventually adapt and continue growing despite treatment.
The findings, published in the peer-reviewed journal EMBO Molecular Medicine, suggest that tumors carrying the gene fusion can bypass their dependence on male hormones by activating an alternative growth pathway driven by cortisol, the body’s primary stress hormone.
Researchers found that when androgen levels are reduced through treatment, tumors with the gene fusion can activate cancer-promoting genes through cortisol receptors, effectively switching to a different biological mechanism for survival and growth.
The team said this is the first time a clear molecular link has been demonstrated between the gene fusion and resistance to hormone therapy.
The findings suggest that in this subset of tumors, blocking androgen signaling alone may not be enough, as cancer cells can shift to a cortisol-driven pathway. Researchers say this identifies a specific molecular target that could potentially be blocked alongside standard hormone therapy.
Promising results in mice
To test the theory, researchers used a mouse model of human prostate cancer and examined a combination treatment that blocks both androgen signaling and cortisol receptor activity.
The combined approach reduced tumor growth and extended survival in the animals, suggesting a possible treatment strategy that warrants further clinical evaluation.
The study also raises questions about the use of steroid-based medications in advanced prostate cancer treatment. Because steroids can activate cortisol receptors, researchers say they may unintentionally help fuel cancer growth in patients with the gene fusion.
“It is also important to be careful when giving steroids to these patients, as they activate the cortisol receptor and may help the cancer,” Yarden said.
The findings point toward a potential shift in treatment strategy for patients carrying the mutation. Rather than relying solely on androgen suppression, future therapies could combine standard hormone treatment with drugs that inhibit cortisol receptor signaling.
Because the gene fusion is present in roughly half of prostate cancer cases, researchers say patients could eventually be screened to identify those most likely to develop treatment resistance, paving the way for more personalized care.
Researchers also noted that cortisol receptor-blocking drugs already exist and may be suitable for repurposing.
“A drug that blocks the cortisol receptor, which showed promising results in our study in mice, was approved last month by the FDA for the treatment of patients with ovarian cancer, and I hope that the success will also be replicated in prostate cancer,” Yarden said.
