Imaging and Modifying Hypoxia in Head and Neck Squamous Cell Tumors

头颈部鳞状细胞肿瘤的缺氧成像和改善

• 批准号: 7464161
• 负责人: Sydney M. Evans
• 金额: $ 27.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-22 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464161
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adjuvant Therapy; Apoptosis; Appendix; Binding; Biological; Biological Assay; Blood Vessels; Brain Neoplasms; Cell Proliferation; Cells; Cervical; Cervical lymph node group; Clinical; Data; Diagnosis; Disease-Free Survival; Dose; EF5; End Point; Finland; Goals; HIV Protease Inhibitors; Head and Neck Cancer; Head and Neck Neoplasms; Head and neck structure; Hypoxia; Image; Imaging Techniques; Immunohistochemistry; Individual; Institution; Invaded; Invasive; Larynx; Malignant Squamous Cell Neoplasm; Measures; Multivariate Analysis; Nelfinavir; Neoplasm Metastasis; Nodal; Operating Rooms; Operative Surgical Procedures; Oral cavity; Oropharyngeal; Outcome; Oxygen; PECAM1 gene; Partial Pressure; Pathway interactions; Patients; Pattern; Personal Satisfaction; Positron-Emission Tomography; Primary Neoplasm; Protocols documentation; Protons; Public Health; Publishing; Quality of life; Radiation; Radiation-Sensitizing Agents; Radioactive; Radiobiology; Recurrence; Relative (related person); Resistance; Rodent; Sampling; Serum; Signal Transduction; Squamous Cell Neoplasms; Staging; Staining method; Stains; Standards of Weights and Measures; Statistically Significant; TNM; Time; Tissues; Treatment outcome; Tumor Oxygenation; Tumor Pathology; Tumor Tissue; Urine; Viral; Work; azomycin; base; cancer therapy; chemotherapy; clinically significant; cohort; day; disorder risk; experience; hypoxia inducible factor 1; improved; lymph nodes; neoplastic cell; osteopontin; pre-clinical; prognostic; protein expression; radiation resistance; resistance factors; treatment duration; tumor; uptake

DESCRIPTION (provided by applicant): The observation that hypoxia is a major cause of treatment resistance in head and neck cancer (HNC) has been well established for almost a decade. At PENN, we have developed invasive (based on immunohistochemistry, IHC) and non-invasive (based on PET) imaging techniques to identify the presence, level and distribution of hypoxia in tissues. The agent used is a 2-nitroimidazole agent, EF5 that was specifically developed as a quantitative hypoxia marker. We have recently shown that the IHC analysis of EF5 in HNC is prognostic for patient outcome. The overall goal of this project is to build on this observation utilizing 18F-EF5 PET imaging to determine the presence and level of hypoxia as a treatment resistance factor. In our first specific aim (SA), patients with de novo HNC will be imaged with 18F-EF5 PET to ascertain whether this signal can be used as a prognostic and predictive marker. All patients will be treated with a standard regime of surgery followed by chemoradiation therapy. Tissue collected at surgery will be used to assay hypoxia-related biological endpoints including HIF1?, proliferation (Ki67), blood vessels (CD31), apoptosis and pAkt (radiation resistance) and osteopontin (OPN) in the urine. In our second SA, we will study 18F-EF5 PET images in recurrent HNC and assess whether nelfinavir (NFV), a clinically used anti-viral therapy for AIDs, can modify tumor oxygen levels. This work is the clinical extension of published observations made in PENN radiation biology labs that NFV is a radiation sensitizer. Biological and patient outcome endpoints, similar to SA1, will be explored. The long-term application of SA1 is to use the levels and patterns of hypoxia for individualized radiation dose escalation. This is particularly relevant at our institution as we will open our Proton therapy facility in 2010. We hope that positive results with NFV (e.g. tumor re-oxygenation) as studied in SA 2, will open a new avenue for adjuvant therapy in HNC. PUBLIC HEALTH RELEVANCE: Hypoxia has been shown to limit the efficacy of all types of cancer therapy including radiation, chemotherapy and even surgery (because hypoxic tumors are more likely to invade and metastasize). In order to overcome these limitations, it is critical to be able to diagnose the presence, patterns and levels of hypoxia in individual patient tumors. The use of the hypoxia imaging agents EF5 (in tissue sections) and 18F-EF5 for PET scanning will define which patients and what therapies will be most effective in order to improve patient outcome and quality of life.

描述（由申请人提供）：近十年来，关于缺氧是头颈癌（HNC）治疗抵抗的主要原因的观察已得到充分证实。在 PENN，我们开发了侵入性（基于免疫组织化学，IHC）和非侵入性（基于 PET）成像技术来识别组织中缺氧的存在、水平和分布。使用的试剂是 2-硝基咪唑试剂 EF5，专门开发作为定量缺氧标记物。我们最近表明，HNC 中 EF5 的 IHC 分析可预测患者的预后。该项目的总体目标是基于这一观察结果，利用 18F-EF5 PET 成像来确定作为治疗抵抗因素的缺氧的存在和水平。在我们的第一个具体目标 (SA) 中，将使用 18F-EF5 PET 对新发 HNC 患者进行成像，以确定该信号是否可以用作预后和预测标记。所有患者都将接受标准手术治疗，然后进行放化疗。手术中收集的组织将用于测定尿液中与缺氧相关的生物学终点，包括 HIF1?、增殖 (Ki67)、血管 (CD31)、细胞凋亡和 pAkt（辐射抗性）和骨桥蛋白 (OPN)。在我们的第二个 SA 中，我们将研究复发性 HNC 中的 18F-EF5 PET 图像，并评估奈非那韦 (NFV)（一种临床用于艾滋病的抗病毒疗法）是否可以改变肿瘤的氧水平。这项工作是 PENN 辐射生物学实验室已发表的观察结果的临床延伸，即 NFV 是一种辐射增敏剂。将探讨与 SA1 类似的生物学和患者结果终点。 SA1的长期应用是利用缺氧的水平和模式进行个体化的辐射剂量递增。这对于我们的机构尤其重要，因为我们将于 2010 年开设质子治疗设施。我们希望 SA 2 中研究的 NFV（例如肿瘤再氧合）的积极结果将为 HNC 辅助治疗开辟一条新途径。公众健康相关性：缺氧已被证明会限制所有类型癌症治疗的疗效，包括放疗、化疗甚至手术（因为缺氧肿瘤更容易侵袭和转移）。为了克服这些限制，能够诊断个体患者肿瘤中缺氧的存在、模式和水平至关重要。使用缺氧显像剂 EF5（在组织切片中）和 18F-EF5 进行 PET 扫描将确定哪些患者和哪种疗法最有效，从而改善患者的治疗结果和生活质量。