Androgen Receptor Addiction

The term oncogene addiction, or “driver mutation” is pretty central to most of the exciting progress being made in drug development for prostate cancer. At the outset, unlike breast cancer, ~95% of men with prostate cancer achieve some sort of remission with simple androgen ablation. This can take the form of surgical castration (orchiectomy), or the same thing can be achieved (lowering the T level in the blood) through administration of gonadotropin hormone releasing hormone analogs. The best known of these is probably leuprolide, but the same thing happens with other analogs, be they agonists, or the more recently marketed antagonist, degarelix. Overall, there is probably little difference which one is used.

The newer drugs are all designed to further inhibit testosterone stimulation in other ways. Examples include the better androgen receptor blockers (AR) like MDV-3100 or ARN-509 which are improvements on the small molecule blockers initially developed like flutamide or the more commonly used bicalutamide. Still in the laboratory phase are potentially even better blockers like a small molecule called EPI-001 that exerts its action not through blocking androgen binding to its receptor, rather blocking the receptor itself from interacting with DNA in the nucleus or with other proteins. Clearly there are many other approaches to the AR that will eventually lead to newer and better drugs. Blocking the cancer cells from making their own testosterone as is done with abiraterone or TAK-700 is a good example.  However, as Peter Nelson outlines in a lovely review article in the Journal of Clinical Oncology this week, additional mechanisms of resistance emerge. He has characterized this as different “states” of prostate cancer cell existence as shown in this figure from his publication:

States of the Androgen Receptor

Of  course it is important to understand that even this level of complexity is far too simple. The feedback loops that are activated when AR is blocked, or when it is no longer active are many and varied and will require a great deal of further work. Already, trials are evaluating mtor inhibitors like temsirolimus in blocking some of these feedback loops.  Nevertheless, it is great to see the increasing knowledge that will lead to suppression of prostate cancer in patients, and as I have often said, in this field if we can keep patients alive long enough to die of a heart attack or some other malady, we can claim it as a “cure”.

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One response to “Androgen Receptor Addiction

  1. Pingback: Should there be “T” under the tree? | prost8blog

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