Study points to new treatment strategy for prostate cancer

Israeli-led researchers have identified a previously underappreciated mechanism that may explain why many prostate cancers stop responding to standard hormone therapy, offering a clearer target for future treatment strategies.

Prostate cancer is among the most commonly diagnosed cancers in men worldwide, with approximately 1.4 million new cases recorded each year globally, according to international cancer registry estimates such as GLOBOCAN. It is typically treated by reducing or blocking male hormones such as testosterone through hormone therapy, often combined with surgery, radiation, or chemotherapy, depending on the stage and progression of the disease.

The study, led by Prof. Yosef Yarden of the Weizmann Institute of Science, focuses on a genetic alteration known as a gene fusion, a mutation in which two separate genes abnormally join to form a single hybrid gene. This alteration is found in about half of prostate cancer cases. While it has been known for roughly two decades, its role in treatment resistance has remained unclear until now.

Prostate cancer typically depends on androgens to grow. Androgens are a group of hormones — most notably testosterone — that regulate male traits and reproductive function. For this reason, standard treatment often aims to reduce or block androgen activity. Although this approach can be effective at first, many tumours eventually adapt and begin growing again despite continued therapy.

The research, published in the peer-reviewed EMBO Molecular Medicine, found that tumours carrying the gene fusion can bypass their dependence on male hormones by activating an alternative survival pathway driven by cortisol, the body’s main stress hormone.

In healthy cells, androgen activity normally suppresses cortisol receptor signalling. However, the researchers found that when androgen levels are reduced through treatment, this suppression is lifted. In tumours with the gene fusion, a protein produced by the altered genes binds to cortisol receptors and activates cancer-promoting genes, effectively enabling the tumour to switch between biological growth pathways.

The researchers said this is the first time a clear molecular link has been demonstrated between the gene fusion and treatment resistance, helping explain why a significant proportion of cases may eventually stop responding to hormone therapy.

The findings suggest that in this subset of tumours, blocking androgen signalling alone may be insufficient, as cancer cells can shift to a cortisol-driven survival pathway. This identifies a specific molecular target that could potentially be blocked alongside standard hormone therapy.

Mouse Model Results

To test this, researchers used a mouse model of human prostate cancer and examined a combination therapy that blocks both androgen signalling and cortisol receptor activity. The combined approach reduced tumour growth over time and extended survival in the animals, suggesting a possible future treatment strategy that warrants clinical evaluation.

The findings also raise a clinical consideration regarding the use of steroid-based medications in advanced prostate cancer. Steroids are commonly used in treatment, but the study suggests they may activate cortisol receptor signalling in patients with the gene fusion and could potentially interfere with therapy effectiveness.

“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, particularly for patients carrying the gene fusion. Rather than relying solely on androgen suppression, future approaches could combine standard hormone therapy with drugs that inhibit cortisol receptor signalling to prevent this escape mechanism.

Because the gene fusion is present in about half of prostate cancer cases, researchers suggest that patients could eventually be screened to identify those most at risk of developing this form of treatment resistance, paving the way for more personalised care.

Researchers also note that cortisol receptor–blocking drugs already exist and could potentially be repurposed for prostate cancer treatment.

“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.