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Interleukin-6 as a therapeutic target in human ovarian cancer.

ABSTRACT: 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 tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies.

SUBMITTER: Coward J

PROVIDER: S-EPMC3182554 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Interleukin-6 as a therapeutic target in human ovarian cancer.

Coward Jermaine J Kulbe Hagen H Chakravarty Probir P Leader David D Vassileva Vessela V Leinster D Andrew DA Thompson Richard R Schioppa Tiziana T Nemeth Jeffery J Vermeulen Jessica J Singh Naveena N Avril Norbert N Cummings Jeff J Rexhepaj Elton E Jirström Karin K Gallagher William M WM Brennan Donal J DJ McNeish Iain A IA Balkwill Frances R FR

Clinical cancer research : an official journal of the American Association for Cancer Research 20110727 18

<h4>Purpose</h4>We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network.<h4>Experimental design</h4>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.<h4>Results</h4>Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 stai ...[more]

PMID: 21795409

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Project description:Background: Increasing evidences have shown that abnormal alternative splicing (AS) events are closely related to the prognosis of various tumors. However, the role of AS in ovarian cancer (OV) is poorly understood. This study aims to explore the correlation between AS and the prognosis of OV and establish a prognostic model for OV. Methods: We downloaded the RNA-seq data of OV from The Cancer Genome Atlas databases and assessed cancer-specific AS through the SpliceSeq software. Then systemically investigated the overall survival (OS)-related AS and splicing factors (SFs) by bioinformatics analysis. The nomogram was established based on the clinical information, and the clinical practicability of the nomogram was verified through the calibration curve. Finally, a splicing correlation network was constructed to reveal the relationship between OS-related AS and SFs. Results: A total of 48,049 AS events were detected from 10,582 genes, of which 1523 were significantly associated with OS. The area under the curve of the final prediction model was 0.785, 0.681, and 0.781 in 1, 3, and 5 years, respectively. Moreover, the nomogram showed high calibration and discrimination in OV patients. Spearman correlation analysis was used to determine 8 SFs significantly related to survival, including major facilitator superfamily domain containing 11, synaptotagmin binding cytoplasmic RNA interacting protein, DEAH-box helicase 35, CWC15, integrator complex subunit 1, LUC7 like 2, cell cycle and apoptosis regulator 1, and heterogeneous nuclear ribonucleoprotein A2/B1. Conclusion: This study provides a prognostic model related to AS in OV, and constructs an AS-clinicopathological nomogram, which provides the possibility to predict the long-term prognosis of OV patients. We have explored the wealth of RNA splicing networks and regulation patterns related to the prognosis of OV, which provides a large number of biomarkers and potential targets for the treatment of OV. Put forward the potential possibility of interfering with the AS of OV in the comprehensive treatment of OV.

Project description:INTRODUCTION:Interleukin-6 (IL-6) is an important growth factor for estrogen receptor-? (ER?)-positive breast cancer, and elevated serum IL-6 is associated with poor prognosis. METHODS:The role of the phosphorylated signal transducer and activator of transcription 3 pathway was investigated in ER?-positive breast cancer. A panel of cell lines was treated with exogenous IL-6. An IL-6 specific gene signature was generated by profiling ten ER?-positive breast cancer cell lines alone or following treatment with 10 ng/mL recombinant IL-6 or human marrow stromal cell-conditioned media, with or without siltuximab (a neutralizing anti-IL-6 antibody) and grown in three-dimensional tumor microenvironment-aligned cultures for 4 days, 5 days, or 6 days. The established IL-6 signature was validated against 36 human ER?-positive breast tumor samples with matched serum. A comparative MCF-7 xenograft murine model was utilized to determine the role of IL-6 in estrogen-supplemented ER?-positive breast cancer to assess the efficacy of anti-IL-6 therapy in vivo. RESULTS:In eight of nine ER?-positive breast cancer cell lines, recombinant IL-6 increased phosphorylation of tyrosine 705 of STAT3. Differential gene expression analysis identified 17 genes that could be used to determine IL-6 pathway activation by combining their expression intensity into a pathway activation score. The gene signature included a variety of genes involved in immune cell function and migration, cell growth and apoptosis, and the tumor microenvironment. Validation of the IL-6 gene signature in 36 matched human serum and ER?-positive breast tumor samples showed that patients with a high IL-6 pathway activation score were also enriched for elevated serum IL-6 (?10 pg/mL). When human IL-6 was provided in vivo, MCF-7 cells engrafted without the need for estrogen supplementation, and addition of estrogen to IL-6 did not further enhance engraftment. Subsequently, we prophylactically treated mice at MCF-7 engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of hMSC expressing human IL-6 and estrogen. CONCLUSION:Given the established role for IL-6 in ER?-positive breast cancer, these data demonstrate the potential for anti-IL-6 therapeutics in breast cancer.

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Interleukin-6 as a therapeutic target in human ovarian cancer.

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Interleukin-6 as a therapeutic target in human ovarian cancer.

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