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Prostate Cancer Researchers Find New Target in Battle against Resistance

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    In a collaborative study led by scientists at the University of California Davis, researchers report that suppressing the orphan nuclear receptor protein ROR-γ with small-molecule compounds could reduce androgen receptor (AR) levels in castration-resistant prostate cancer and stop tumor growth.

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  This unique approach does not look to target the AR directly, which currently is a widely used strategy, but instead inhibits the gene that codes for the AR protein. The investigators believe that reducing AR levels could help patients overcome treatment-resistant prostate cancer and even rescue existing therapies.


Prostate Cancer.webp

    “This is a new target and a new way of hitting prostate cancer,” explained senior study author Hongwu Chen, Ph.D., professor in biochemistry and molecular medicine at UC Davis. “This strategy targets the root cause of the problem—the overexpression of the AR gene and its protein.”

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 The findings from this study were published recently in Nature Medicine in an article entitled “ROR-γ Drives Androgen Receptor Expression and Represents a Therapeutic Target in Castration-Resistant Prostate Cancer.”


    AR gene expression goes into overdrive for many prostate cancer cases, increasing tumor growth and driving metastasis. The use of antiandrogen therapies can slow, and even stop, prostate cancer—for a time. However, the AR gene often mutates to resist the therapy regimen.


    Yet, the UC Davis team found that suppressing ROR-γ circumvents resistance because the protein product is required for AR gene expression. The researchers showed that ROR-γ inhibition sharply reduced AR protein levels in tumor cells, leading them to hypothesize that preventing AR protein synthesis would allow ROR-γ antagonists to short-circuit the resistance process.


    “Essentially all existing therapies work on blocking either activation of the AR or the genes it regulates,” noted co-author Christopher Evans, M.D., professor and chairman of the Urology department at UC Davis. “However, as patients become resistant to existing agents, the AR becomes mutated, amplified, and spliced. This (ROR-γ suppression) mechanism blocks the true expression of the AR and its spliced forms.”


    To demonstrate the relationship between ROR-γ and the AR gene, the research team studied several small molecule ROR-γ antagonists, both in cell lines and human tumors in mice. In each model, the suppression of ROR-γ reduced AR gene expression and protein levels, blocking tumor growth.


    “Blocking ROR-γ re-sensitizes castration-resistant prostate cancer to drugs that directly inhibit AR pathway signaling, such as enzalutamide,” remarked Dr. Evans. “A combination approach can potentially be very effective.”


    The investigators found that ROR-γ suppression reduced the prevalence of several known oncogenes and lowered AR levels.


    “ROR-γ suppression is quite remarkable,” stated lead study author Junjian Wang, Ph.D., a project scientist in the biochemistry and molecular medicine department at UC Davis. “It can reduce levels of ERG and MYC, which are known to drive prostate cancer.”


    ROR-γ was not seen as a typical candidate for cancer studies—however, it has been a high-value target for autoimmune diseases. As a result, several ROR-γ antagonists are in the pipeline, which could be retasked to fight prostate and possibly other cancers.


    “ROR-γ has been extensively studied as a target for rheumatoid arthritis, inflammatory bowel disease, psoriasis, and other autoimmune conditions,” noted Dr. Chen. “Some drugs are orally available and safe in early clinical trials. They could be a great help for patients with advanced prostate cancer.”

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