Mechanism regulating ErbB signaling network in head and neck cancer

头颈癌ErbB信号网络的调控机制

基本信息

批准号：
8968833
负责人：
RANDALL H KRAMER
金额：
$ 39.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-05 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8968833
关键词：
3-Dimensional Address Adhesions Aggressive behavior Apoptotic Cancer Patient Cell Line Cell Survival Cells Cessation of life Clinical Clinical Research Clinical effectiveness Communities Complex Development Diagnostic Disease Distant Metastasis Epidermal Growth Factor Receptor ErbB Receptor Family Protein Evolution Family Family member Fostering Future Goals Growth Growth Factor Receptors Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Health Hour Human Hypoxia Intercellular Junctions Island Lead Ligands Link Malignant - descriptor Malignant Neoplasms Mediating Metastatic Neoplasm to Lymph Nodes Molecular Molecular Profiling Molecular Target NRG1 gene Neoplasm Metastasis Operative Surgical Procedures Oral Pathological Staging Patients Pharmaceutical Preparations Phosphotransferases Population Primary Neoplasm Process Radiation therapy Receptor Signaling Recurrence Regulation Reporting Resistance Resistance development Signal Pathway Signal Transduction Solid Neoplasm Squamous cell carcinoma Survival Rate Testing Therapeutic Tumorigenicity Tyrosine Kinase Inhibitor Variant Work Xenograft procedure autocrine cancer cell cancer diagnosis cell growth chemotherapeutic agent chemotherapy density dimer disorder control inhibitor/antagonist interest malignant mouth neoplasm mouth squamous cell carcinoma neoplastic cell novel novel therapeutic intervention novel therapeutics outcome forecast overexpression patient subsets prognostic promoter receptor receptor expression targeted treatment treatment strategy tumor tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Invasive squamous cell carcinoma is the most common malignant tumor of the upper aerodigestive tract. Despite advances in surgical and radiotherapeutic approaches for therapy, the overall prognosis of oral and head and neck cancer remains poor primarily due to its aggressive invasive capacity, recurrence, and local and distant metastases. Oral squamous cell carcinomas with regional metastasis have a survival rate close to 50%. There is an urgent need to develop novel molecular targets that yield new effective therapeutic approaches. Squamous cell carcinomas present as tightly associated nests of three-dimensional tumor with extensive cell-cell junctional adhesions that permit cell growth and resistance to apoptotic insults. Our findings implicated the involvement of intercellular adhesions in conferring this protection and revealed that cell-cell contacts provide discrete cell survival signaling. The overall goal of this project is to define the mechanisms that regulate growth factor receptor signaling profiles that lead to more aggressive oral SCC cell populations and to identify how complex cellular microenvironmental interrelationships contribute to development of resistance to inhibitors targeting ErbB axis family members. Recent clinical studies have examined the prognostic relevance of overexpressed ErbB3 in HNSCC and report that elevated ErbB3 correlates with metastatic disease and poor overall patient survival. This project focuses specifically on the overriding hypothesis that in oral SCC development, high-density three-dimensional nests of tumor cells promote shifts in specific ErbB family signaling profiles favoring enhanced proliferation and tumor progression. Aim 1 will investigate how the 3D-tumor microenvironment regulates cell growth. Aim 2 will identify the mechanism controlling ErbB receptor profile in tumor foci. Aim 3 will define the importance of HIF-1α induction of ErbB receptor expression in tumor progression. These proposed studies should foster an increased understanding of the evolution of aggressive HNSCC that could be exploited for the future development of novel therapeutic strategies.

描述（由申请人提供）：侵袭性鳞状细胞癌是上呼吸消化道最常见的恶性肿瘤，尽管手术和放射治疗方法取得了进展，但口腔癌和头颈癌的总体预后仍然较差，这主要是由于其侵袭性。侵袭能力、复发率以及局部和远处转移的口腔鳞状细胞癌的生存率迫切需要接近50%。开发新的分子靶点，产生新的有效治疗方法。鳞状细胞癌呈现为紧密相关的三维肿瘤巢，具有广泛的细胞-细胞连接粘附，允许细胞生长和抵抗细胞凋亡损伤。该项目的总体目标是确定调节生长因子受体信号传导谱的机制，从而导致更具攻击性的口腔鳞状细胞癌细胞群，并确定其复杂程度。细胞微环境的相互关系有助于针对 ErbB 轴家族成员的抑制剂产生耐药性。最近的临床研究检查了 HNSCC 中过度表达的 ErbB3 的预后相关性，并报告说，ErbB3 升高与转移性疾病和患者总体生存率较差相关。最重要的假设是，在口腔鳞状细胞癌的发展中，肿瘤细胞的高密度三维巢促进特定 ErbB 家族信号传导谱的转变，有利于增强增殖和肿瘤进展。将研究 3D 肿瘤微环境如何调节细胞生长。目标 2 将确定肿瘤病灶中控制 ErbB 受体谱的机制。目标 3 将确定 HIF-1α 诱导 ErbB 受体表达在肿瘤进展中的重要性。加深对侵袭性 HNSCC 进化的了解，可用于未来开发新的治疗策略。