Studies explore resistance to hormone therapy in prostate cancer

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“The study highlights the importance of considering how altering cell metabolism could impact prostate cancer and its response to treatment," says Jenna Giafaglione.

Studies led by investigators at the University of California, Los Angeles (UCLA) offer insights that may help identify patients with prostate cancer who are less likely to respond to treatment with hormone therapy, according to a news release from UCLA.1

The second study, published in Cell Reports, assessed prostate cancer cells’ responses when the androgen receptor pathway is blocked.

The second study, published in Cell Reports, assessed prostate cancer cells’ responses when the androgen receptor pathway is blocked.

The first study, published in Nature Cell Biology, demonstrated that tumors that are less luminal are more resistant to hormone therapy compared with tumors that are more luminal, which are more treatable.2

Further, the investigators found that inhibition of the mitochondrial pyruvate carrier (MPC) and supplementation with exogenous lactate resulted in altered responses to antiandrogen therapy, which may potentially affect the success of treatments. The authors suggest that MPC inhibition and lactate accumulation may make prostate tumors more resistant to androgen receptor inhibition.

“The study highlights the importance of considering how altering cell metabolism could impact prostate cancer and its response to treatment. If we know that certain aspects of metabolism are promoting a resistant phenotype, then we can go after new targets in those resistant tumors,” said lead author Jenna Giafaglione in the news release.1 Giafaglione is a graduate student in UCLA’s Molecular Biology Interdepartmental Program and member of the Goldstein lab as well as the lab of Paul Boutros, the director of cancer data science at the UCLA Jonsson Comprehensive Cancer Center.

The second study, published in Cell Reports, assessed prostate cancer cells’ responses when the androgen receptor pathway is blocked, specifically in terms of their energy production and usage.3 The findings showed that response to androgen receptor inhibition is characterized by reduced glycolysis, elongation of the mitochondria, and increased reliance on mitochondrial oxidative metabolism, which was shown to support prostate cancer growth and survival.

The investigators identified a key protein, called MYC, which serves as a regulator in the cells’ initial dependence on a type of energy inside the mitochondria. They found that when MYC decreased as a result of therapy, cancers cell became very reliant on the mitochondria to survive. However, if therapy did not lower MYC, the cells became resistant to treatment and not reliant on their mitochondria.

The reactivation of MYC reversed the androgen receptor inhibition-mediated reduction in glycolysis and prevented sensitivity to complex I inhibition, making the cells less sensitive to certain inhibitors, according to the authors.

“This study teaches us about treatment response and also suggests that if we could find the right combination of therapies, for example, to use hormone therapy initially, and then to use some kind of secondary therapy that influences the mitochondrial behavior, we might be able to reduce disease progression and recurrence,” said senior author Andrew S. Goldstein, PhD, in the news release.1 Goldstein is a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

According to the news release, findings from both studies demonstrate the need for more research on the link between metabolism and treatment response in prostate cancer.

References

1. Studies help explain why some prostate cancers become resistant to hormone therapy. News release. University of California, Los Angeles (UCLA), Health Sciences. December 1, 2023. Accessed December 6, 2023. https://www.newswise.com/articles/studies-help-explain-why-some-prostate-cancers-become-resistant-to-hormone-therapy

2. Giafaglione JM, Crowell PD, Delcourt AML, et al. Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment. Nat Cell Biol. Published online December 4, 2023. doi:10.1038/s41556-023-01274-x

3. Crowell PD, Giafaglione JM, Jones AE, et al. MYC is a regulator of androgen receptor inhibition-induced metabolic requirements in prostate cancer. Cell Rep. 2023;42(10):113221. doi:10.1016/j.celrep.2023.113221

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