Hormone-blocking breakthrough helps combat skin cancer recurrence

Monash University

A Monash University researcher has helped discover how to reduce the recurrence of skin cancer tumours by blocking a naturally-occurring hormone that causes drug resistance in melanoma cells.

Studies showed that by blocking androgens – the ‘male’ sex hormones – with the drug enzalutamide, melanoma cells were more sensitive to drugs designed to inhibit cancer growth.

The findings could have significant implications for patients with advanced melanoma, and other cancers, as conventional treatments only reduce, not eliminate, the risk of tumour recurrence after surgery. This is because cancer cells eventually develop resistance once the disease has spread.

The study’s co-first author, Dr Miles Andrews from the Monash Central Clinical School, carried out the research alongside a team at University of Texas’ MD Anderson Cancer Center. Dr Andrews said the findings – published in the journal Nature last week – revealed a new way to improve the efficacy of BRAF targeted therapy, a common drug used in almost half of all advanced skin cancer patients.

“BRAF targeted therapy acts to block a key growth signal in melanoma cells to which the melanoma cells have effectively become addicted,” said Dr Andrews, who is also a medical oncologist with The Alfred Cancer Program.

“We discovered that androgens – the ‘male’ sex hormones – appear to provide a parallel signal to melanoma cells that confers a degree of resistance to BRAF inhibition, thus reducing the clinical benefit from these drugs.

“In mouse models, by treating melanomas with both BRAF targeted therapy and a potent androgen-blocking drug called enzalutamide, we achieved better melanoma control than was possible with the targeted therapy alone.”

The mouse research was conducted to further understand the link between sex hormones and cancer response to therapy. It followed clinical studies that revealed differences in how male and female melanoma patients respond to BRAF targeted therapy drugs.

The studies showed female patients who received the drug in conjunction with melanoma surgery were twice as likely as men to remain cancer free. Their recurrence-free survival rate two years after surgery was 64 per cent, compared to 32 per cent among male patients.

Dr Andrews said the findings showed a link between androgen – which is naturally higher in males – and cancer-drug resistance.

“We discovered that BRAF targeted therapy can promote increased levels of androgen receptor protein, but these receptors don’t last long unless their hormone is present as well. Thus, we think the interaction between androgen signalling and BRAF targeted therapy is particularly active in males, because androgen hormone levels are naturally high in males.”

Dr Andrews said clinical trials combining androgen blockade with BRAF targeted therapy would be critical to evaluating the potential of a dual treatment strategy for melanoma patients.

“There is very exciting data emerging that androgen signalling also interacts with cancer immunotherapy, so this entire field studying how sex hormones affect cancer treatment has enormous potential to benefit many patients with a wide range of cancers.”

Read the full paper in Nature titled: Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

https://doi.org/10.1038/s41586-022-04833-8

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