Mechanisms of Perineural Invasion in Head and Neck Cancer

头颈癌神经周围侵犯的机制

• 批准号: 8751977
• 负责人: Seungwon Kim
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8751977
• 关键词: Address; Affect; Antibodies; Binding; Biological Assay; Cell Communication; Cell Line; Cells; Clinical; Clinical Trials; Coculture Techniques; Databases; Disease; Down-Regulation; ERBB2 gene; ERBB3 gene; Embryonic Development; Epidermal Growth Factor Receptor; Family; Focal Adhesion Kinase 1; Foundations; Future; Genetic; HER2 inhibition; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Life; Ligands; Mediating; Mediator of activation protein; Medical center; Modality; Modeling; Movement; Mus; Nerve; Neuregulin 1; Neurites; Neurons; Operative Surgical Procedures; Patients; Process; Protein Tyrosine Kinase; Radiation therapy; Receptor Protein-Tyrosine Kinases; Recurrence; Role; Schwann Cells; Signal Transduction; Specimen; Spinal Ganglia; Survival Rate; Testing; Therapeutic; Therapeutic antibodies; Treatment outcome; Tumor Bank; Tumor Cell Invasion; Tyrosine Kinase Domain; Universities; base; case control; cell motility; cellular imaging; chemotherapy; cohort; effective therapy; head and neck cancer patient; improved; in vitro Model; member; migration; myelination; neoplastic cell; neuron development; novel; outcome forecast; paracrine; perineural; public health relevance; receptor; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinoma (HNC) is a disease that affects over 50,000 patients every year. A hallmark of aggressive HNC is its propensity to spread along nerves, a process termed perineural invasion (PNI) that is found in up to 40% of patient. It has been demonstrated that patients with PNI have significantly higher rates of locoregional recurrence and lower overall survival. Although HNC patients with PNI often receive all of the currently available therapy (surgery, chemotherapy, and radiotherapy), the overall survival rates of these patients are still significantly lower than those without PNI. Attempts at developing novel agents that target PNI have been hampered by the lack of understanding of the factors that regulate this process. Such efforts have been further hindered by the lack of in vitro models that can reliably recapitulate the major features of PNI by HNC cells. In order to bride this gap, we have recently developed a novel in vitro model of PNI based on murine dorsal root ganglia. To our knowledge, this neurite-tumor cell interaction (NTI) assay is the only assay that has successfully reproduced the invasion and migration of HNC cells along cultured neurites. Utilizing the NTI assay, we have identified neuregulin 1(NRG1), a known ligand of HER3 (a member of the ErbB receptor tyrosine kinase family that also include epidermal growth factor receptor (EGFR) and HER2), as a mediator of the HNC cell-neurite interaction. Our findings showed that HNC cells express HER3 and that the activation of HER3 by NRG1 results in the formation of HER2:HER3 heterodimers. This is followed by the activation of Src and focal adhesion kinase (Fak), and by the increased migration and invasion of the HNC cells. Co-culture of HNC cells and neurons also resulted in increased migration and invasion of HNC cell that was dependent on HER3. More importantly, the NTI assay showed that the attraction and movement of HNC cells to and along neurites is inhibited by HER3 antibodies. Therefore, we hypothesize that PNI in HNC is mediated by the paracrine activation of HER3 on tumor cells by neuronal NRG1 where HER3 targeting may be an effective therapeutic strategy. We will test this hypothesis with the following two separate but interrelated aims: i) to determine the importance of NRG1:HER3 axis in mediating PNI in HNC, and ii) to determine the whether HER2 blockade is essential for HER3 targeted inhibition of PNI. In order to study these aims, we will take advantage of our unique NTI assay, availability of tumor specimens from our institutional HNC tumor bank, and clinical available HER2 and HER3 antibodies. By demonstrating NRG1 and HER3 to be a mediator of PNI in HNC, we hope to elucidate a therapeutic target for a clinical problem against which we have no effective therapy. The completion of this study will also lay the foundation for future clinical trials of anti-ErbB agent in improving the prognosis of HNC patients with PNI.

描述（由申请人提供）： 头颈鳞状细胞癌 (HNC) 是一种每年影响超过 50,000 名患者的疾病。侵袭性 HNC 的一个标志是其沿着神经扩散的倾向，这一过程被称为神经周围侵犯 (PNI)，高达 40% 的患者会发现这种情况。研究表明，PNI 患者的局部复发率明显较高，总体生存率较低。尽管合并 PNI 的 HNC 患者通常会接受目前所有可用的治疗（手术、化疗和放疗），但这些患者的总生存率仍显着低于未合并 PNI 的患者。由于缺乏对调节这一过程的因素的了解，开发针对 PNI 的新型药物的尝试受到了阻碍。由于缺乏能够可靠地重现 HNC 细胞 PNI 主要特征的体外模型，此类努力进一步受到阻碍。为了弥补这一差距，我们最近开发了一种基于小鼠背根神经节的新型 PNI 体外模型。据我们所知，这种神经突-肿瘤细胞相互作用 (NTI) 测定是唯一成功重现 HNC 细胞沿培养神经突侵袭和迁移的测定。利用 NTI 测定，我们鉴定出神经调节蛋白 1 (NRG1)，一种 HER3 的已知配体（ErbB 受体酪氨酸激酶家族的成员，还包括表皮生长因子受体 (EGFR) 和 HER2），作为 HNC 细胞的介质-神经突相互作用。我们的研究结果表明，HNC 细胞表达 HER3，并且 NRG1 激活 HER3 导致 HER2:HER3 异二聚体的形成。随后是 Src 和粘着斑激酶 (Fak) 的激活，以及 HNC 细胞迁移和侵袭的增加。 HNC 细胞和神经元的共培养还导致 HNC 细胞依赖于 HER3 的迁移和侵袭增加。更重要的是，NTI 测定表明 HNC 细胞向神经突的吸引和运动受到 HER3 抗体的抑制。因此，我们假设 HNC 中的 PNI 是由神经元 NRG1 旁分泌激活肿瘤细胞上的 HER3 介导的，其中 HER3 靶向可能是一种有效的治疗策略。我们将通过以下两个独立但相互关联的目标来检验这一假设： i) 确定 NRG1:HER3 轴在介导 HNC 中 PNI 中的重要性，以及 ii) 确定 HER2 阻断是否对于 HER3 靶向抑制 PNI 至关重要。为了研究这些目标，我们将利用我们独特的 NTI 检测、来自我们机构 HNC 肿瘤库的肿瘤样本以及临床可用的 HER2 和 HER3 抗体。通过证明 NRG1 和 HER3 是 HNC 中 PNI 的介质，我们希望为我们尚无有效疗法的临床问题阐明治疗靶点。本研究的完成也将为未来抗ErbB药物改善HNC合并PNI患者预后的临床试验奠定基础。