Prostate cancer drugs could treat melanoma in men

Researchers from the University of Pennsylvania have shown that testosterone promotes melanoma proliferation by activating a nonclassical testosterone receptor in melanoma cells called ZIP9, a zinc transporter that is not intentionally targeted by any available therapeutics but is widely expressed in human melanoma.

Using melanoma models in mice, the team showed that drugs that target androgen receptors (AR) in prostate cancer can be effectively repurposed to block ZIP9 and thereby inhibit melanoma in men. Their work has been published in the journal Cancer Research.

Melanoma and most other cancers occur more frequently, and have worse outcomes, in men compared to women. While this sex difference has been recognised for decades, the reasons for the difference have largely remained elusive. While sex steroids are thought to be involved, the classical androgen and oestrogen receptors generally considered necessary for sex steroid effects are not detectable in most melanomas.

“The male sex hormone testosterone increases the rate of melanoma cell proliferation because it acts through ZIP9 rather than through the classical testosterone receptors that are well studied in prostate cancer,” said Associate Professor Todd Ridky, senior author on the new study. “While there are no approved drugs that inhibit ZIP9, structurally related drugs such as apalutamide that block the classical testosterone/androgen receptor in prostate cancer, when given to mice with melanoma, slowed tumour growth and extended survival, but only in males.”

The discovery is likely applicable to most human melanomas, with the researchers having examined 98 human melanocytic lesions (regular moles, as well as primary and metastatic melanoma from both males and females). Nearly all samples expressed lots of ZIP9, while the classical testosterone receptor was not detectable in any of them. ZIP9 is also expressed in many other human tissues, suggesting that the discovery may be broadly applicable to many cancer types.

This study is said to be the first to show that ZIP9 is a determinant of the male vs female disparity in cancer, and establishes a novel mechanistic link between male androgens and melanoma pathobiology. These findings also build on prior work from the Ridky lab, where researchers have shown that oestrogen signalling through a nonclassical oestrogen receptor called G protein-coupled oestrogen receptor (GPER) suppresses melanoma and other cancers.

With regard to some cancers and sex hormones, biological males seem to be disadvantaged twice: they lack the protective effects of nonclassical oestrogen activity, while testosterone, through ZIP9, actively makes the tumours worse. The potential good news is that both of these sex steroid receptors are likely druggable. While more clinical trials are needed, currently approved prostate cancer drugs seem to effectively block ZIP9.

Image credit: ©stock.adobe.com/au/Africa Studio

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