PARD3 Alterations, Circulating Tumors Cells and Metastasis in Head and Neck Cance

PARD3 改变、循环肿瘤细胞和头颈癌的转移

基本信息

批准号：
7989506
负责人：
Stephen Michael Rothenberg
金额：
$ 13.66万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7989506
关键词：
Abnormal Cell Aftercare Antibodies BCL2 gene Biological Markers Biology Blood Blood Cells CCND1 gene Cancer Etiology Cancer cell line Cell Adhesion Cell Line Cell Polarity Cells Cessation of life Chicago Clinical Combined Modality Therapy Cytokeratin Detection Development Disease Distant Metastasis EGFR gene Epithelial Cells Event Exons Fluorescent in Situ Hybridization Gene Silencing General Hospitals Genes Genotype Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Health Histology Human Immunofluorescence Microscopy Immunohistochemistry Immunoprecipitation In Vitro Keratin Lead Link Malignant Epithelial Cell Malignant Neoplasms Maps Mass Spectrum Analysis Massachusetts Measures Methods Monitor Morbidity - disease rate Mus Mutation Neoplasm Metastasis Oncogenic Outcome PTPRC gene Patient Care Patients Phenotype Population Prevalence Primary Neoplasm Proteins Public Health RNA Interference Recurrence Resistance Resolution Risk Role Single Nucleotide Polymorphism Site Solid Neoplasm Specimen Squamous Cell Squamous cell carcinoma Staging Structure TP53 gene Time Tissues Tumor Cell Invasion Tumor Suppression Universities Variant Work Xenograft procedure base c-erbB-1 Proto-Oncogenes gain of function improved in vivo loss of function migration neoplastic cell new technology outcome forecast peripheral blood public health relevance research study response therapeutic target tissue culture tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Head and Neck Squamous Cell Carcinoma (SCCHN) is one of the most common cancers worldwide and a significant cause of cancer morbidity and deaths. Although SCCHN is unique among solid tumors in that the majority of patients present with local disease, metastasis remains a critical problem for SCCHN treatment: patients without metastases can be cured; patients with metastases cannot. Even for local disease, despite improvements in outcome with intensive, multimodality therapies, such treatments are highly toxic, poorly tolerated and only partially efficacious. Long-term survival is only ~ 50%, with most patients dying from their cancers. There is an urgent need to uncover the critical genetic alterations in SCCHN and to determine how these impact patient outcome and metastatic risk. To search for genes that are critical for head and neck squamous carcinoma (SCCHN) biology, prognosis and therapy, I have initially used high resolution single nucleotide polymorphism (SNP) arrays to detect copy number alterations in 684 human cancer cell line of diverse tissue origin, including SCCHN. This analysis has identified recurrent homozygous deletions involving >200 genes. Among these, PARD3, encoding a critical regulator of cell polarity, is disrupted in squamous carcinoma cell lines and primary tumors, including from the head and neck region. Since abnormal cell polarity has been linked to increased migration and metastasis, these findings may implicate loss of function of PARD3 or its downstream effectors in the risks of recurrence and metastasis of a subset of these cancers. The overall goals of this proposal are: (1) to further characterize the role of PARD3 in SCCHN tumorigenesis, migration and metastasis; and (2) to capture and genotype circulating tumor cells (CTCs) from the peripheral blood of patients with SCCHN, to determine if CTCs can identify patients at risk for metastases before metastatic disease is clinically apparent. The experiments will utilize primary tumors and peripheral blood from patients treated for SCCHN, as well as PARD3 loss-of-function and gain-of-function squamous cell lines for in vitro and in vivo studies to identify the cancer-related phenotype(s) controlled by PARD3 and the domains and activities required for tumor suppression. By characterizing PARD3 loss in the tumor type in which inactivating mutations have arisen as a primary event during tumor formation, this work will directly implicate alterations in cell polarity in the development and invasive and metastatic potential of these cancers. By capturing and molecularly characterizing CTCs in actual SCCHN patients undergoing treatment, this work will permit the real time in vivo analysis of tumor cells to quantify clinical risk and guide treatment. As a result, these studies may lead to improved biomarkers and suggest potential new targets for therapies, thus providing benefit to public health by improving the care of patients with these cancers. PUBLIC HEALTH RELEVANCE: Although cancers of the head and neck pose a significant health problem worldwide, how they develop is incompletely understood, existing treatments are only partially effective and safely measuring whether treatments actually target the tumor cells in the patients being treated is very difficult. We have discovered frequent loss of a single gene, PARD3, in human head and neck cancers that could permit cells to loosen from each other, move through the blood to different sites and thereby evade detection and resist treatment. By determining whether patients possessing cancers which have lost PARD3 do worse with treatment, how PARD3 contributes to cancer formation and spread, and whether the tumor cells present in patients' blood can be captured and used to measure the benefit of treatment, the experiments outlined in this proposal may lead to better and less toxic treatments.

描述（由申请人提供）：头颈鳞状细胞癌（SCCHN）是世界范围内最常见的癌症之一，也是癌症发病和死亡的重要原因。尽管SCCHN在实体瘤中具有独特性，大多数患者表现为局部病变，但转移仍然是SCCHN治疗的关键问题：无转移的患者可以治愈；转移患者不能。即使对于局部疾病，尽管强化、多模式治疗的结果有所改善，但此类治疗具有高毒性、耐受性差且仅部分有效。长期生存率仅为 50%，大多数患者死于癌症。迫切需要揭示 SCCHN 的关键基因改变，并确定这些改变如何影响患者的治疗结果和转移风险。为了寻找对头颈鳞癌 (SCCHN) 生物学、预后和治疗至关重要的基因，我最初使用高分辨率单核苷酸多态性 (SNP) 阵列来检测 684 个不同组织来源的人类癌细胞系中的拷贝数变化，包括 SCCHN。该分析已识别出涉及超过 200 个基因的反复出现的纯合缺失。其中，编码细胞极性关键调节因子的 PARD3 在鳞状癌细胞系和原发性肿瘤（包括头颈区域）中被破坏。由于异常的细胞极性与迁移和转移的增加有关，这些发现可能表明 PARD3 或其下游效应器的功能丧失与这些癌症的一部分复发和转移的风险有关。该提案的总体目标是：（1）进一步表征PARD3在SCCHN肿瘤发生、迁移和转移中的作用； (2) 从 SCCHN 患者的外周血中捕获循环肿瘤细胞 (CTC) 并进行基因分型，以确定 CTC 是否可以在临床上出现转移性疾病之前识别出有转移风险的患者。该实验将利用来自接受 SCCHN 治疗的患者的原发性肿瘤和外周血，以及 PARD3 功能丧失和功能获得的鳞状细胞系进行体外和体内研究，以确定与癌症相关的表型由 PARD3 以及肿瘤抑制所需的结构域和活性控制。通过表征肿瘤类型中 PARD3 的缺失（其中失活突变是肿瘤形成过程中的主要事件），这项工作将直接暗示这些癌症的发展以及侵袭和转移潜力中细胞极性的改变。通过捕获和分子表征正在接受治疗的实际 SCCHN 患者的 CTC，这项工作将允许对肿瘤细胞进行实时体内分析，以量化临床风险并指导治疗。因此，这些研究可能会改进生物标志物，并提出潜在的新治疗靶点，从而通过改善这些癌症患者的护理来为公众健康带来益处。公共健康相关性：尽管头颈癌在全世界范围内构成了严重的健康问题，但它们的发展方式尚不完全清楚，现有的治疗方法仅部分有效，并且安全地测量治疗方法是否真正针对接受治疗的患者的肿瘤细胞非常困难。我们发现，在人类头颈癌中，单个基因 PARD3 经常缺失，这可能导致细胞彼此松散，通过血液移动到不同部位，从而逃避检测并抵制治疗。通过确定患有失去 PARD3 的癌症的患者是否会在治疗中表现更差，PARD3 如何促进癌症的形成和扩散，以及患者血液中存在的肿瘤细胞是否可以被捕获并用于衡量治疗的益处，实验概述于这一提议可能会带来更好、毒性更低的治疗方法。