Todd William Ridky, M.D., Ph.D., Physician Scientist, Associate Professor of Dermatology at the Pearlman School of Medicine, University of Pennsylvania speaks about Drugs Designed for Prostate Cancer Show Promise for Treating Melanoma in Men.
Link to Article:
https://www.pennmedicine.org/news/news-releases/2021/october/drugs-designed-for-prostate-cancer-show-promise-for-treating-melanoma-in-men
According to current research, testosterone enhances melanoma proliferation in melanoma cells by activating ZIP9 (encoded by the SLC39A9 gene), a zinc transporter that is not intentionally targeted by any known treatments but is abundantly expressed in human melanoma. Researchers at the University of Pennsylvania’s Perelman School of Medicine used melanoma models in mice to demonstrate that medications that target androgen receptors (AR) in prostate cancer can be effectively repurposed to block ZIP9 and so prevent melanoma in men. The research was published in the journal Cancer Research today.
Men are more likely than women to develop melanoma and most other malignancies, and they have worse results. In 2021, the American Cancer Society predicts that 106,110 new melanomas will be diagnosed in the United States (62,260 men and 43,850 women), with 7,180 people dying from the illness (about 4,600 men and 2,580 women). While the gender gap has been acknowledged for decades, the causes for it have remained mostly unknown. While sex steroids are thought to be involved, most melanomas lack the traditional androgen and estrogen receptors that are thought to be required for sex steroid actions.
Most human melanomas are anticipated to benefit from this discovery about ZIP9. The researchers studied 98 human melanocytic lesions (regular moles, as well as primary and metastatic melanoma from both males and females). The traditional testosterone receptor was not detectable in any of the samples, although nearly all of them expressed a lot of ZIP9. Because ZIP9 is expressed in a variety of human organs, this finding in melanoma could be applied to a variety of cancers.
This is the first study to indicate that ZIP9 is a determinant of cancer disparities between men and women, and it provides a unique molecular relationship between male androgens and melanoma pathobiology. These findings add to previous research from Penn’s Ridky lab, which found that estrogen signaling via a nonclassical estrogen receptor called G protein-coupled estrogen receptor (GPER) suppresses melanoma and other malignancies.
In the case of some cancers and sex hormones, biological males appear to be at a disadvantage twice: they lack the preventive effects of nonclassical estrogen action, while testosterone, via ZIP9, actively worsens tumors. Both of these sex steroid receptors are presumably druggable, which is potentially good news. While further research is needed, presently licensed prostate cancer medications appear to be effective in blocking ZIP9.
The research was funded by NIH/NCI funds (R01 CA163566, 11 R41CA228695) and the Dermatology Foundation’s Stiefel award. The Penn Skin Biology and Diseases Resource-based Center (P30- 13 AR069589), the Melanoma Research Foundation, and the Department of Defense all contributed to this research.