The anti‐interleukin‐6 antibody siltuximab down‐regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study

Karkera, Jayaprakash D.; Steiner, Hannes; Liu, Weimin; Skradski, Viktor; Moser, Patrizia; Riethdorf, Sabine; Reddy, Manjula; Puchalski, Thomas A.; Safer, Karim; Prabhakar, Uma; Pantel, Klaus; Qi, Ming; Čulig, Zoran

doi:10.1002/pros.21362

Cited by 102 publications

(65 citation statements)

References 33 publications

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“…IL-6 antagonism may potentially be successful in the treatment of cancer, and a fully humanized anti-IL-6 antibody (1339 Mab, GlaxoSmithKline, Boronia, Australia) inhibited the growth and invasion of multiple myeloma in a SCID-hu mouse model [54]. Given the central role of IL-6 in the vicious cycle of solid tumor growth, it is encouraging that phase I/II clinical trials are currently underway in the treatment of ovarian, pancreatic, colorectal, head and neck and lung cancer using a newly developed IL-6 antibody CNTO 328 (Centocor, NCT00841191) and positive reports are emerging for its use in metastatic renal cell and prostate cancer [55,56].…”

Section: Discussionmentioning

confidence: 99%

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Hugo

Lebret

Tomaskovic-Crook

et al. 2012

Cancer Microenvironment

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Hyperactive inflammatory responses following cancer initiation have led to cancer being described as a 'wound that never heals'. These inflammatory responses elicit signals via NFκB leading to IL-6 production, and IL-6 in turn has been shown to induce epithelial to mesenchymal transition in breast cancer cells in vitro, implicating a role for this cytokine in cancer cell invasion. We previously have shown that conditioned medium derived from cancerassociated fibroblasts induced an Epithelial to Mesenchymal transition (EMT) in PMC42-LA breast cancer cells and we have now identify IL-6 as present in this medium. We further show that IL-6 is expressed approximately 100 fold higher in a cancer-associated fibroblast line compared to normal fibroblasts. Comparison of mouse-specific (stroma) and human-specific (tumor) IL-6 mRNA expression from MCF-7, MDA MB 468 and MDA MB 231 xenografts also indicated the stroma rather than tumor as a significantly higher source of IL-6 expression. Mast cells (MCs) feature in inflammatory cancer-associated stroma, and activated MCs secrete IL-6. We observed a higher MC index (average number of mast cells per xenograft section/average tumor size) in MDA MB 468 compared to MDA MB 231 xenografts, where all MC were observed to be active (degranulating). This higher MC index correlated with greater mouse-specific IL-6 expression in the MDA MB 468 xenografts, implicating MC as an important source of stromal IL-6. Furthermore, immunohistochemistry on these xenografts for pSTAT3, which lies downstream of the IL-6 receptor indicated frequent correlations between pSTAT3 and mast cell positive cells. Analysis of publically available databases for IL-6 expression in patient tissue revealed higher IL-6 in laser capture microdissected stroma compared to adjacent tissue epithelium from patients with inflammatory breast cancer (IBC) and invasive non-inflammatory breast cancer (non-IBC) and we show that IL-6 expression was significantly higher in Basal versus Luminal molecular/phenotypic Microenvironment (2012) 5:83-93 DOI 10.1007 groupings of breast cancer cell lines. Finally, we discuss how afferent and efferent IL-6 pathways may participate in a positive feedback cycle to dictate tumor progression.

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Section: Discussionmentioning

confidence: 99%

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Hugo

Lebret

Tomaskovic-Crook

et al. 2012

Cancer Microenvironment

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“…In a phase I study, 20 patients scheduled for radical prostatectomy received either no drug or siltuximab (6 mg/kg, 5 patients/group with administration once, twice, and three times, prior to surgery). A decrease in phosphorylation of Stat3 transcription factor and p44/p42 MAPKs, with a downregulation of genes immediately downstream of the IL6 signaling pathway and key enzymes of the androgen signaling pathway, was observed (69). A phase II study designed by SWOG was completed in chemotherapy-pretreated patients with castration-resistant prostate cancer, showing stable disease in 7 patients (23%).…”

Section: Prostate Cancermentioning

confidence: 99%

Interleukin-6 as a Therapeutic Target

Rossi

Liu²,

Jourdan

et al. 2015

Clinical Cancer Research

313

277

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Human IL6 is a cytokine produced by many cell types that has pleiotropic effects. In agreement, anti-IL6 therapy reduces inflammation, hepatic acute phase proteins, and anemia and has antiangiogenic effects. Blocking IL6 has demonstrated therapeutic efficacy with drug registration in Castleman disease and inflammatory diseases (rheumatoid arthritis) without major toxicity. Interestingly, the inhibition of C-reactive protein (CRP) production is a trustworthy surrogate marker of anti-IL6 therapy efficacy. Clinically registered IL6 inhibitors include siltuximab, an anti-IL6 mAb, and tocilizumab, an anti-IL6R mAb. In various cancers, in particular plasma cell cancers, large randomized trials showed no efficacy of IL6 inhibitors, despite a full inhibition of CRP production in treated patients in vivo, the numerous data showing an involvement of IL6 in these diseases, and initial short-term treatments demonstrating a dramatic inhibition of cancer cell proliferation in vivo. A likely explanation is the plasticity of cancer cells, with the presence of various subclones, making the outgrowth of cancer subclones possible using growth factors other than IL6. In addition, current therapeutic strategies used in these cancers already target IL6 activity. Thus, anti-IL6 therapeutics are able to neutralize IL6 production in vivo and are safe and useful in inflammatory diseases and Castleman disease.

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“…Consequently, STAT3-activating cytokines, such as IL6, are of much interest. In particular, antibodies that neutralize IL6 or block IL6 receptor (R) a are in clinical trials for ovarian, prostate, and renal cancers (7,8). In an orthotopic nude endometrial carcinoma model, IL6 promoted tumor growth (9), while targeted inhibition of the IL6 receptor dramatically reduced tumor growth in HEC1A cell-derived subcutaneous xenografts in immunodeficient mice (10).…”

Section: Introductionmentioning

confidence: 99%

Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo

Winship

Sinderen

Donoghue

et al. 2016

Molecular Cancer Therapeutics

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Endometrial cancer contributes to significant morbidity and mortality in women with advanced stage or recurrent disease. IL11 is a cytokine that regulates cell cycle, invasion, and migration, all hallmarks of cancer. IL11 is elevated in endometrial tumors and uterine lavage fluid in women with endometrial cancer, and alters endometrial epithelial cancer cell adhesion and migration in vitro, but its role in endometrial tumorigenesis in vivo is unknown. We injected mice subcutaneously with human-derived Ishikawa or HEC1A endometrial epithelial cancer cells (ectopic), or HEC1A cells into the uterus (orthotopic) to develop endometrial cancer mouse models. Administration of anti-human IL11 receptor (R) a blocking antibody dramatically reduced HEC1A-derived tumor growth in both models and reduced peritoneal metastatic lesion spread in the orthotopic model, compared with IgG. Anti-human IL11Ra retained a well-differentiated, endometrial epithelial phenotype in the HEC1A ectopic mice, suggesting it prevented epithelial-to-mesenchymal transition. Blockade of mouse IL11Ra with anti-mouse IL11Ra antibody did not alter tumor growth, suggesting that cancer epithelial cell IL11 signaling is required for tumor progression. In vitro, anti-human IL11Ra antibody significantly reduced Ishikawa and HEC1A cell proliferation and invasion and promoted apoptosis. Anti-human, but not anti-mouse, IL11Ra antibody reduced STAT3, but not ERK, activation in HEC1A cells in vitro and in endometrial tumors in xenograft mice. We demonstrated that targeted blockade of endometrial cancer epithelial cell IL11 signaling reduced primary tumor growth and impaired metastasis in ectopic and orthotopic endometrial cancer models in vivo. Our data suggest that therapeutically targeting IL11Ra could inhibit endometrial cancer growth and dissemination. Mol Cancer Ther; 15(4); 720-30. Ó2016 AACR.

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The anti‐interleukin‐6 antibody siltuximab down‐regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study

Abstract: Preliminary safety of siltuximab is favorable. Future studies in which siltuximab could be combined with androgen-deprivation therapy and experimental therapies in advanced prostate cancer are justified.

Cited by 102 publications

References 33 publications

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Contribution of Fibroblast and Mast Cell (Afferent) and Tumor (Efferent) IL-6 Effects within the Tumor Microenvironment

Interleukin-6 as a Therapeutic Target

Targeting Interleukin-11 Receptor-α Impairs Human Endometrial Cancer Cell Proliferation and Invasion In Vitro and Reduces Tumor Growth and Metastasis In Vivo

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