ROR-γ: a new way to suppress androgen receptor expression?


Most of our readers will be familiar with the idea that progression of prostate cancer over time is associated with the expression of  androgen receptors (ARs) in prostate cancer tissue.

Once prostate cancer leaves the prostate and starts the process of metastasis, standard forms of androgen deprivation therapy like LHRH agonists, antiandrogens, and other agents can be used initially to block the effects of testosterone and dihydrotestosterone on the growth of the cancer, which slows down progression. Newer drugs like abiraterone acetate and enzalutamide act more directly on the AR pathway to slow disease progression as well, and other forms of AR antagonist are also in development. But … what if one could actually block expression of the ARs — either partially or entirely?

A new paper by Wang et al. in Nature Medicine is suggesting that this may be a real possibility.

Wang and his colleagues at the University of California, Davis have discovered that a biochemical known as retinoic acid receptor-related orphan receptor gamma (which is a bit of a mouthful, so it’s abbreviated to ROR-γ or ROR-gamma) is over-expressed and amplified in metastatic, castration-resistant prostate cancer (mCRPC) tumors, and that ROR-γ drives AR expression in the tumors.

They have also been able to show that ROR-γ antagonists are able to

  • Suppress expression of AR (and of the variant AR-V7) in prostate cancer cell lines and tumors
  • Diminish genome-wide AR binding and expression of the AR target gene network
  • Suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft models of prostate cancer
  • Sensitize CRPC tumors to enzalutamide, without overt toxicity, in mice

Some regular readers will remember that the AR-V7 variant type of prostate cancer is usually resistant to treatment with both enzalutamide (Xtandi) and abiraterone acetate (Zytiga).

Additional information about this study can be found in a media release from the University of California, Davis, that has been reproduced on the ScienceDaily web site. Obviously there is a lot more research that will be needed if we are to be able to turn this set of scientific findings into effective and safe treatments for progressive prostate cancer, but the finding is certainly an interesting one. As Wang et al. also write:

Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced [prostate cancer].

2 Responses

  1. FYI to all readers, the Johns Hopkins proprietary test for AR V7 that may indicate suitability for abiraterone and/or enzalutamide was made publicly available in the past month. There is more information here and the Johns Hopkins requisition form for your doctor’s signature can be printed from here

    The cost is $1,000. It is not clear yet if this is covered by insurance, although logically it would make sense and save insurance companies a good deal of money.

    Onward and upwards,

    rd

  2. Does anyone have other examples of ROR-gamma antagonists that are underway? I read that they are being studied but don’t see anything published. Thanks!

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