Editors' ChoiceCancer

Thinking Outside the Box in Prostate Cancer

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Science Translational Medicine  08 Dec 2010:
Vol. 2, Issue 61, pp. 61ec189
DOI: 10.1126/scitranslmed.3001989

One of the first examples of targeted cancer therapy was Huggins’ Nobel Prize–winning work that demonstrated that castration (or androgen deprivation) led to clinical benefit in prostate cancer patients. We now know that castration works by disabling the function of the androgen receptor (AR) protein, which is activated by androgens. However, despite androgen deprivation, lethal, castration-resistant prostate cancers (CRPC) commonly emerge. Most efforts to overcome CRPC focus on further lowering levels of androgens that persist in tumors despite castration or directly inhibiting the function of the androgen receptor (AR) protein. New work by Tanaka et al. shows that the N-cadherin protein, which is associated with epithelial-to-mesenchymal (EMT) transition, is also a promising target in prostate cancer.

The authors first used gene expression microarrays in matched non-CRPC and CRPC cell lines to show that the N-cadherin gene was commonly upregulated with castration. These findings were confirmed in human tumor samples. They next demonstrated that N-cadherin promotes invasion, EMT, and migration of prostate cancer cells, whether or not these cells express the AR, through modulation of Akt, transforming growth factor–β, and other key signaling pathways. Because N-cadherin is a cell-surface molecule, the authors tested monoclonal antibodies to N-cadherin as potential therapies. Treatment of castrated mice implanted with N-cadherin overexpressing CRPC cells with these antibodies abolished castration-resistant growth of tumors and led to apoptosis. Lastly, treatment of castrated mice implanted with non-CRPC cells with these antibodies blocked progression to CRPC.

This work demonstrates that although great progress has been made in prostate cancer research and treatment because of the field’s focus on androgens and AR signaling, thinking outside this box may allow for the development of new and more effective therapies. The next question is whether these results extend to the treatment of humans cancer patients and, if so, will targeting N-cadherin be safe and effective in the 32,000 men who die from incurable CRPC each year?

H. Tanaka et al., Monoclonal antibody targeting N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat. Med. 7 November 2010 (10.1038/nm.2236). [Abstract]

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