Editors' ChoiceCancer

Sinking Prostate Cancer from Under the Sea

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Science Translational Medicine  23 Jun 2010:
Vol. 2, Issue 37, pp. 37ec98
DOI: 10.1126/scitranslmed.3001358

Over 27,000 men will die of castration-resistant prostate cancers this year. This is despite androgen-deprivation therapy, our most effective treatment for recurrent prostate cancer, which works by lowering levels of androgens or interfering with androgen binding to and activation of the ligand-binding domain of the androgen receptor protein. The amino terminal domain of androgen receptor is another key motif, and extrinsic pathways such as interleukin-6 (IL-6) and epidermal growth factor activate the androgen receptor amino terminal domain in an androgen-independent manner. However, effective approaches to target the androgen receptor amino terminal domain have remained elusive.

Now, Andersen et al. screened marine sponge extracts in order to identify inhibitors of the androgen receptor amino terminal domain and found that one extract, EPI-001, achieved this effect in the low-micromolar-concentration range. In subsequent experiments, they demonstrated that EPI-001 specifically inhibited androgen receptor amino terminal domain transactivation in cells overexpressing a functional androgen receptor expression vector containing an amino terminal domain but lacking the ligand binding domain. However, it did not impair activation of other nuclear hormone receptors, highlighting its specificity. The inhibitor-reduced expression of androgen target genes, through impaired androgen receptor binding to its androgen response elements, prevented androgen-induced proliferation and caused regression of prostates in nude mice and CRPC xenografts in nude mice without apparent toxicity.

In vitro, EPI-001 and bicalutamide (a commonly prescribed androgen antagonist) had similar effects on prostate cancer growth. EPI-001 was not directly compared in vivo with bicalutamide or new, more potent forms of androgen deprivation therapy. However, we now know that androgen-independent androgen receptor splice variants, which are resistant to androgen-deprivation therapy, exist and that resistance eventually develops even despite treatment with newer forms of androgen-deprivation therapy. For these reasons, EPI-001—a drug discovered from under the sea—has promise to sink prostate cancer, including the lethal castration-resistant form of the disease.

R.J. Andersen et al., Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 17, 535–546 (2010). [Abstract]

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