Targeting the IL-6 pathway in combination with cetuximab in head and neck squamous cell carcinoma

靶向 IL-6 通路联合西妥昔单抗治疗头颈鳞状细胞癌

• 批准号: 9397121
• 负责人: Rachel O'Keefe
• 金额: $ 3.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9397121
• 关键词: Address; Affect; Binding; Biological Assay; Blocking Antibodies; Cell Line; Cell Proliferation; Cell Survival; Cells; Cetuximab; Clinic; Clinical; Complex; Cytolysis; Data; Development; Diagnosis; EGFR Protein Overexpression; Epidermal Growth Factor Receptor; Erbitux; FDA approved; Face; Flow Cytometry; Genetic; Glycocalyx; Head and Neck Squamous Cell Carcinoma; Human; IL6 gene; Immune; Immunocompetent; Immunosuppression; Immunosuppressive Agents; Interleukin 6 Receptor; Interleukin-6; Laboratories; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Monoclonal Antibodies; Natural Killer Cells; Oncogenic; PDCD1LG1 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Pre-Clinical Model; Proteins; Receptor Inhibition; Resistance; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Stat3 protein; Survival Rate; Testing; Therapeutic; Treatment Efficacy; antibody-dependent cell cytotoxicity; antitumor effect; base; cancer therapy; cytokine; improved; inhibiting antibody; inhibitor/antagonist; knock-down; mRNA Expression; mouse model; neoplastic cell; pre-clinical; preclinical study; resistance mechanism; response; targeted agent; targeted treatment; therapeutic target; therapy resistant; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. The approximately 600,000 patients diagnosed with HNSCC each year face a five-year survival rate of only 50%, a statistic that has not improved significantly in decades. Despite the increasing use of targeted therapies in cancer treatment, cetuximab (Erbitux), a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), is one of only three targeted agents that are FDA approved for treatment of HNSCC. Resistance to cetuximab-containing therapy remains a major obstacle; thus, identification and targeting of mediators of cetuximab resistance is needed to improve patient outcomes. Although a number of mechanisms of resistance to cetuximab have been identified in preclinical studies, these efforts have not yet resulted in a co-targeting strategy that has proven effective in overcoming cetuximab resistance in the clinic. Cetuximab exerts its antitumor effects by inhibiting EGFR-mediated activation of tumor cell proliferation and survival pathways and by inducing antibody-dependent cell-mediated cytotoxicity (ADCC), in which natural killer (NK) cells, a type of innate immune cell, induce lysis of tumor cells coated with cetuximab. One potential mediator of cetuximab resistance is interleukin 6 (IL-6), a cytokine that promotes tumor cell proliferation and survival and has a number of immunosuppressive functions in the tumor microenvironment. Our preliminary data suggest that expression of IL-6 is increased in cetuximab-resistant HNSCC cells and that these cells are sensitive to inhibition of the IL-6 pathway. Based on this and other preclinical and clinical evidence supporting a role for IL-6 in cetuximab resistance, we hypothesize that IL-6 mediates resistance to cetuximab both by offsetting the effects of EGFR inhibition in tumor cells and by impeding the ability of NK cells to mediate lysis of cetuximab- opsonized tumor cells. To test this hypothesis, I will assess the antitumor efficacy of combining EGFR- and IL-6 pathway-targeted therapies in preclinical models of HNSCC. I will also analyze the effects of IL-6 on cetuximab-induced ADCC and determine whether inhibition of IL-6 signaling can enhance the ability of NK cells to mediate cetuximab-induced ADCC. These studies will elucidate the role of IL-6 in cetuximab resistance and may provide support for the use of inhibitors of the IL-6 pathway in combination with cetuximab as a therapeutic strategy for HNSCC.

项目摘要/摘要 头颈部鳞状细胞癌（HNSCC）是全球第六大癌症。这 每年大约有600,000名被诊断出患有HNSCC的患者面临的五年生存率仅为50％，A 几十年来尚未显着改善的统计数据。尽管越来越多地使用靶向疗法 癌症治疗，西妥昔单抗（Erbitux），一种抑制表皮生长因子受体的单克隆抗体 （EGFR）是FDA批准用于治疗HNSCC的仅有的三种靶向药物之一。抵抗 含西妥昔单抗的疗法仍然是主要障碍。因此，识别和靶向调解人 需要西妥昔单抗耐药性来改善患者预后。虽然多种电阻机制 在临床前研究中已经确定了西妥昔单抗，这些努力尚未导致共同目标 证明有效克服诊所中西妥昔单抗抵抗的策略。西妥昔单抗发挥作用 通过抑制EGFR介导的肿瘤细胞增殖和存活途径的激活和抗肿瘤作用 通过诱导抗体依赖性细胞介导的细胞毒性（ADCC），其中天然杀伤（NK）细胞是一种类型的细胞 先天免疫细胞，诱导用西妥昔单抗覆盖的肿瘤细胞的裂解。西妥昔单抗的一个潜在介体 抗性是白介素6（IL-6），一种促进肿瘤细胞增殖和存活的细胞因子，具有A 肿瘤微环境中免疫抑制功能的数量。我们的初步数据表明 在抗Cetuximab的HNSCC细胞中，IL-6的表达增加，这些细胞对 抑制IL-6途径。基于此和其他临床前和临床证据，支持了 在西妥昔单抗抗性中IL-6，我们假设IL-6通过抵消了对西妥昔单抗的抗性。 EGFR抑制在肿瘤细胞中的影响，并通过阻碍NK细胞介导西妥昔单抗裂解的能力 调整肿瘤细胞。为了检验这一假设，我将评估组合EGFR和的抗肿瘤功效 HNSCC的临床前模型中的IL-6途径为靶向疗法。我还将分析IL-6对 西妥昔单抗诱导的ADCC并确定IL-6信号的抑制是否可以增强NK的能力 细胞介导西妥昔单抗诱导的ADCC。这些研究将阐明IL-6在西妥昔单抗抗性中的作用 并可能为使用IL-6途径的抑制剂与西妥昔单抗一起提供支持 HNSCC的治疗策略。