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25-11-2010 | Oncology | Article

N-cadherin antibodies may delay castration-resistant prostate cancer

Abstract

Free abstract

MedWire News: Monoclonal antibodies specific to the protein N-cadherin could delay prostate cancer metastasis and progression to castration resistance, reports a team of scientists.

Their findings also suggest that tumor regression may be induced by these antibodies.

The primary cause of death among men with prostate cancer is the development of metastatic disease that is resistant to androgen deprivation therapy, explains the team.

Seeking to identify alternative pathways to castration resistance, Robert Reiter, from the University of California, Los Angeles, USA, and colleagues conducted a series of investigations using prostate cancer cell cultures, mice transplanted with androgen-dependent and castration-resistant prostate cancer cells, and tissue samples obtained from men who died from prostate cancer.

The team reports in the journal Nature Medicine that N-caherin expression was absent in hormone-sensitive prostate cancer cells but present in castration resistant cells. Human tissue samples also indicated that expression was 1% in benign prostatic hyperplasia, 9.5% in hormone-naïve disease, 22.5% in cancer treated with neoadjuvant androgen deprivation, and 41% in castration-resistant disease.

Mouse models revealed that N-cadherin expression was sufficient to cause epithelial-to-mesenchymal transition, invasion, and metastasis, and was necessary for castration-resistant growth, potentially leading to an inverse loss of the androgen receptor.

The team then developed two monoclonal antibodies against N-cadherin, which slowed invasion, attachment, and proliferation in both castration-resistant prostate cancer cell lines, and in mouse models of castration-resistant prostate cancer, as well as delaying the time to castration resistance.

In large established tumors from the PCS cell line, prolonged administration of the antibodies led to long-term growth suppression and improvements in survival, while dose escalation to 20 mg per kg body weight led to complete regression in over 50% of tumors.

Furthermore, anti-N-cadherin antibodies led to progressive declines in serum interleukin-8 levels and reductions in the serine-threonine protein kinase Akt, which may partially explain the anti-tumor activity.

The researchers conclude: "The finding that N-cadherin-targeted antibodies delay castration-resistant progression and inhibit growth, invasion, and metastasis raises the possibility that these antibodies may be translatable to the clinic."

Reiter added: "This therapy may be particularly useful in men who are failing the newest forms of treatment that target the androgen receptor, which regulates testosterone."

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

By Liam Davenport

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