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Jun 27, 2013
 |  BC Innovations  |  Cover Story

Agonizing switch in prostate cancer

Aragon Pharmaceuticals Inc. researchers have uncovered how a specific androgen receptor mutation results in turning second-generation antagonists for prostate cancer into agonists.1 The results could allow the company, which is being acquired by Johnson & Johnson, to develop third-generation molecules that overcome the resistance mechanism.

Antiandrogen drugs were the first targeted therapy approved for prostate cancer and have substantially improved survival rates for patients. However, many castration-resistant prostate cancers (CRPCs) become resistant to antiandrogens because of elevated androgen receptor expression or mutation.2

Second-generation antiandrogens are effective against prostate cancers resistant to first-generation drugs because they antagonize both the overexpressed and the mutated receptors. These include marketed drug Xtandi enzalutamide, from Astellas Pharma Inc. and Medivation Inc., and Aragon's ARN-509, which is in Phase II testing.

Like with first-generation molecules, the duration of the therapeutic response to Xtandi or ARN-509 is limited because patients develop resistance to these compounds.

"With the selective pressure from therapeutics in cancer treatment, drug resistance seems inevitable. We need to determine whether we can anticipate and deal with drug resistance preemptively in the drug design and development process, instead of waiting to react," said Yang Shen, a research assistant professor at the Toyota Technological Institute at...

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