An international team of researchers led by Weizmann Institute scientists uncovers a key reason for prostate cancer drug resistance and shows how a combination of existing drugs may eliminate this resistance.
Almost all prostate cancers depend on androgens – male sex hormones, including testosterone – for their survival. Therefore, it is common to treat this cancer by castration, i.e. reducing the production levels of sex hormones or blocking their activity, in order to stop the growth. However, this effect is usually short-lived, and resistance to treatment often develops and the cancer returns.
In a new study, the findings of which are published today in the scientific journal EMBO Molecular MedicineAn international research team, led by Israel Prize laureate Prof. Yosef Jordan from the Department of Immunology and Biological Regeneration at the Weizmann Institute of Science, a central reason for the development of this resistance. The study shows that a common genetic change – an abnormal fusion between two genes that characterizes about half of prostate cancer cases – allows the cancer to bypass its dependence on sex hormones and rely instead on a different type of steroid hormone: cortisol – the body’s main stress hormone. Using a mouse model of human prostate cancer, the researchers, led by Dr. Arunchalam Skar, showed that a combination therapy focused on inhibiting both male sex hormones and the hormone cortisol, suppresses the tumor over time and extends life. These findings mark a new therapeutic direction for a significant proportion of prostate cancer patients.
Beyond the new therapeutic potential, the findings also raise a warning sign regarding the use of steroids in cases of prostate cancer. Today, many cases of advanced prostate cancer are treated with steroids, and the study suggests that this treatment, which is intended to suppress the cancer, may actually help it in some cases.
Between fusion and healing
It was discovered about two decades ago that a fusion of two genes characterizes about half of prostate cancer cases. The new study, which was based in part on data from human patients obtained in collaboration with the US National Cancer Institute (NCI) in Bethesda, Maryland, revealed for the first time how the fused gene leads to the development of resistance to the standard treatment protocol. The researchers showed that the fused gene produces a protein that binds to cortisol receptors and together they activate genes that promote the cancer process. Under normal conditions, the presence of male sex hormones suppresses the action of cortisol receptors and the discovered pathway remains silent, but cancer treatment by suppressing sex hormones activates this alternative pathway and leads to cancer resistance.
"It will now be possible to try the combination treatment in human patients with the fused gene," says Prof. Yarden. "It is also important to be careful when giving steroids to these patients, as they activate the cortisol receptor and may help the cancer. 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."
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