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Prostate Cancers Hijack Our Circadian Rhythm To Evade Anti-Hormonal Therapy

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Hormone therapy can keep metastatic prostate cancer well under control, but sooner or later tumor cells become resistant to it. Unexpectedly, a possible solution has now emerged: drugs that are not designed to fight cancer at all, but which influence the day-and-night rhythm of a cell. Professor Wilbert Zwart is part of the international team of researchers, led by the Antoni van Leeuwenhoek institute, that is publishing a report on this discovery in the renowned journal Cancer Discovery today.

Prostate cancer is a type of cancer that grows under the influence of hormones, primarily testosterone. Patients with metastatic prostate cancer are therefore often treated with anti-hormonal therapy, which inhibits the growth-stimulating signal of testosterone and, therefore, tumor growth.

Hormone Therapy

Anti-hormonal therapy can control prostate cancer well, but eventually the drug stops working since the tumor cells become resistant. The greatest challenge in the treatment of metastatic prostate cancer is, therefore, not to find drugs that combat tumor growth but to find drugs that can prevent resistance. How exactly this process of resistance to hormone therapy works in the tumor cell, however, has been a mystery until now.

Preventing Resistance

This international research team, consisting of researchers from the Antoni van Leeuwenhoek institute, TU/e and the Oncode Institute, has now made a surprising discovery in the tissue of patients with prostate cancer treated with a testosterone-inhibiting drug. An unexpected class of proteins, namely proteins that normally regulate the day-and-night rhythm, was found to nullify the effects of the anti-hormonal therapy. "A prostate cancer cell no longer has a day-and-night rhythm," says Wilbert Zwart, one of the research leaders. "But these 'day-night rhythm' proteins have now acquired an entirely new function in tumor cells: they keep the tumor cell alive despite hormone therapy. This had never been seen before."

Now that researchers have discovered this escape route from the tumor, they want to start developing strategies to block it, with the goal of further increasing the efficacy of anti-hormonal therapy against prostate cancer.

Zwart continues, "The discovery has taught us that for new drugs in the treatment of prostate cancer we need to start thinking outside the usual box, to start testing drugs that influence day-night rhythm proteins, in order to increase the sensitivity for hormonal therapy in prostate cancer. Fortunately, there are already several therapies that affect the day-night rhythm. These can be combined with anti-hormonal therapies. This advance, which makes a form of drug repurposing possible, could save ten years of research."

Research set-up

The research was performed in the tissue of 56 patients with high-risk prostate cancer. They received anti-hormonal therapy for three months before their surgery and then their tissue was examined at DNA level. "We then saw that genes that, despite the treatment, can keep the tumor cell alive had suddenly come under the control of proteins that normally regulate the day-and-night rhythm," says researcher Simon Linder, who is due to receive his PhD for the research. However, this surprising discovery also opens up new opportunities, as inhibition of these day-and-night proteins was found to further increase sensitivity to anti-hormonal therapy both in tumor cells in the lab and in mice.

The results of the research may raise the question of whether a disturbed day-and-night rhythm due to shift work, for example, can increase the risk of therapy insensitivity in prostate cancer. "There is no evidence for this," says internist-oncologist André Bergman. "In prostate tumor cells, in fact, the day and night rhythm no longer functions. The protein has acquired a completely new function here. This new escape route of the tumor cell now has our full attention. Follow-up research will show whether inhibition of this improves the treatment of prostate cancer."

Reference: Linder S, Hoogstraat M, Stelloo S, et al. Drug-induced epigenomic plasticity reprograms circadian rhythm regulation to drive prostate cancer towards androgen-independence. Cancer Discov. 2022:candisc.0576.2021-5-3 12:14:47.513. doi: 10.1158/2159-8290.CD-21-0576


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