Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer

作者：Jermaine Coward, Hagen Kulbe, Probir Chakravarty, David P. Leader, Vessela Vassileva, David A. Leinster, R. Thompson, Tiziana Schioppa, Jeffery Nemeth, Jessica Vermeulen, Naveena Singh, Norbert Avril, Jeff Cummings, Elton Rexhepaj, Karin Jirström, William M. Gallagher, Donal J. Brennan, Iain A. McNeish, Frances R. Balkwill · 发表于：Clinical Cancer Research · 年份：2011 · DOI：10.1158/1078-0432.ccr-11-0945 · 被引用次数：390 · 研究领域：Cytokine Signaling Pathways and Interactions、Chemokine receptors and signaling、Immune cells in cancer

PURPOSE: We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. EXPERIMENTAL DESIGN: We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. RESULTS: Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. CONCLUSION: IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the t...