Adaptive Upregulation of EGFR Limits Attenuation of Tumor Growth by Neutralizing IL6 Antibodies, with Implications for Combined Therapy in Ovarian Cancer

Milagre, Carla; Gopinathan, Ganga; Everitt, Gemma; Thompson, Richard G.; Kulbe, Hagen; Zhong, Haihong; Hollingsworth, Robert E.; Grose, Richard; Bowtell, David D.L.; Hochhauser, Daniel; Balkwill, Frances R.

doi:10.1158/0008-5472.can-14-1801

Cited by 41 publications

(30 citation statements)

References 36 publications

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“…Most therapeutic antibodies have failed in phase II/III clinical trials due to the lack of biomarkers to identify the subset of patients most likely to benefit from a specific targeted therapy. A few studies have reported that cells compensate for the presence of a neutralizing antibody by activating another oncogenic signaling pathway . According to these reports, it is worth investigating the targeting of multiple pathways with companion biomarkers, such as targeting both VEGF and IL‐6 or both EGFR and IL‐6.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic loss of heparan sulfate 3‐O‐sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis

Huang

Chen

et al. 2018

Intl Journal of Cancer

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Precision medicine requires markers for therapeutic guidance. The purpose of this study was to determine whether epithelial ovarian cancer (EOC) epigenetics can lead to the identification of biomarkers for precision medicine. Through integrative methylomics, we discovered and validated the epigenetic signature of NEFH and HS3ST2 as an independent prognostic factor for type II EOC in our dataset (n = 84), and two independent methylomics datasets (total n = 467). Integrated transcriptomics dataset (n = 1147) and tissue microarrays (n = 54) of HS3ST2 also related to high-methylation statuses and the EOC prognosis. Mechanistic explorations of HS3ST2 have assessed responses to oncogenic stimulations such as IL-6, EGF, and FGF2 in cancer cells. The combination of HS3ST2 and various oncogenic ligands also confers the worse outcome. 3-O-sulfation of heparan sulfate by HS3ST2 makes ovarian cancer cells intrinsically sensitive to oncogenic signals, which sheds new light on the application of HS3ST2 as a companion diagnostic for targeted therapy using kinase inhibitors or therapeutic antibodies.

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Section: Discussionmentioning

confidence: 99%

Epigenetic loss of heparan sulfate 3‐O‐sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis

Huang

Chen

et al. 2018

Intl Journal of Cancer

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“…Increased IL6 secretion and consequent autocrine survival signaling were also found to be a cause of drug resistance to the EGFR inhibitor, erlotinib, in NSCLC (12). Conversely, IL6 antibody treatment can upregulate EGFR expression and limit ovarian tumor growth inhibition (39). This suggests that a combined approach blocking both the EGFR and IL6 pathways may improve response and counteract resistance.…”

Section: Discussionmentioning

confidence: 99%

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

Zhong¹,

Davis²,

Ouzounova

et al. 2016

Cancer Research

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Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for IL6 in promoting tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Notably, in tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2

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“…The AOCS1 cell line was kindly given by Professor David Bowtell (Peter MacCallum Cancer Centre, Melbourne, Australia) and was established from the ascites of a patient diagnosed with HGSOC, Silverberg Grade 3, after second relapse.The G33 cell line was established in our laboratory from an omental HGSOC tumor collected during interval debulking surgery in 2011 (16). The cell lines have been authenticated.…”

Section: Methodsmentioning

confidence: 99%

A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases

Montfort

Pearce

Maniati

et al. 2017

Clinical Cancer Research

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175

136

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Purpose In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T-cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the antitumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the antitumor immune response in HGSOC metastases. Experimental Design Unmatched pre and post-chemotherapy HGSOC metastases were studied. B-cell localization was assessed by immunostaining. Their cytokines and chemokines were measured by a multiplex assay, and their phenotype was assessed by flow cytometry. Further in vitro and in vivo assays highlighted the role of B cells and plasma cell IgGs in the development of cytotoxic responses and dendritic cell activation. Results B cells mainly infiltrated lymphoid structures in the stroma of HGSOC metastases. There was a strong B-cell memory response directed at a restricted repertoire of antigens and production of tumor-specific IgGs by plasma cells. These responses were enhanced by chemotherapy. Interestingly, transcript levels of CD20 correlated with markers of immune cytolytic responses and immune complexes with tumor-derived IgGs stimulated the expression of the costimulatory molecule CD86 on antigen-presenting cells. A positive role for B cells in the antitumor response was also supported by B-cell depletion in a syngeneic mouse model of peritoneal metastasis. Conclusions Our data showed that B cells infiltrating HGSOC omental metastases support the development of an antitumor response.

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Adaptive Upregulation of EGFR Limits Attenuation of Tumor Growth by Neutralizing IL6 Antibodies, with Implications for Combined Therapy in Ovarian Cancer

Cited by 41 publications

References 36 publications

Epigenetic loss of heparan sulfate 3‐O‐sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis

Epigenetic loss of heparan sulfate 3‐O‐sulfation sensitizes ovarian carcinoma to oncogenic signals and predicts prognosis

A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors

A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases

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