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：
8589584
负责人：
RANDALL H KRAMER
金额：
$ 39.35万
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 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8589584
关键词：
3-Dimensional Abbreviations Address Adhesions Aggressive behavior Apoptotic Cancer Patient Cell Line Cell Survival Cells Cessation of life Clinical Clinical Research Clinical effectiveness Communities Complex Cycloheximide Development Diagnostic Disease Distant Metastasis EGF gene 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 Heregulin Hour Human Hypoxia Immunoprecipitation Intercellular Junctions Island Lead Ligands Link Malignant - descriptor Malignant Neoplasms Mediating 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 diagnosis cell growth chemotherapeutic agent chemotherapy density dimer disorder control hypoxia inducible factor 1 inhibitor/antagonist interest lymph nodes malignant mouth neoplasm monolayer mouth squamous cell carcinoma neoplastic cell novel novel therapeutics outcome forecast overexpression prognostic promoter public health relevance receptor receptor expression 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-1? 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很差，这主要是由于其侵袭性侵袭能力、复发以及局部和远处转移。具有区域转移的口腔鳞状细胞癌的生存率接近50%。迫切需要开发新的分子靶点来产生新的有效治疗方法。鳞状细胞癌表现为紧密相连的三维肿瘤巢，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。我们的研究结果表明细胞间粘附参与了这种保护，并揭示了细胞与细胞的接触提供了离散的细胞存活信号。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，从而导致更具侵袭性的口腔 SCC 细胞群，并确定复杂的细胞微环境相互关系如何促进针对 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 ErbB3 过度表达的预后相关性，并报告 ErbB3 升高与转移性疾病和患者总体生存率较差相关。该项目特别关注最重要的假设，即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。目标 1 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 将定义 HIF-1 的重要性？诱导肿瘤进展中的 ErbB 受体表达。这些拟议的研究应促进人们对侵袭性头颈部鳞状细胞癌的演变有更多的了解，从而可用于未来开发新的治疗策略。