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）：观察到缺氧是头颈癌（HNC）耐药性的主要原因（HNC）的主要原因已有近十年了。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，以识别组织中缺氧的存在，水平和分布。所使用的试剂是一种2-硝基咪唑剂EF5，该剂是专门作为定量缺氧标记的。我们最近表明，HNC中EF5的IHC分析对患者预后是预后的。该项目的总体目标是利用18F-EF5 PET成像来确定缺氧作为治疗抗性因子的存在和水平。在我们的第一个特定目的（SA）中，将使用18F-EF5 PET成像从头hnc的患者，以确定该信号是否可以用作预后和预测标记。所有患者将通过标准的手术方案进行治疗，然后进行化学放疗治疗。手术时收集的组织将用于测定与缺氧相关的生物学终点，包括HIF1？，增殖（KI67），血管（CD31），凋亡和PAKT（抗辐射性）和骨髓蛋白骨蛋白（OPN）（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Nelfinavir（NFV）是临床使用的抗病毒疗法的NELFINAVIR（NFV）是否可以改变肿瘤氧水平。这项工作是宾夕法尼亚州辐射生物学实验室中发表的观察结果的临床扩展，即NFV是辐射敏化剂。将探索与SA1相似的生物学和患者结果终点。 SA1的长期应用是将缺氧的水平和模式用于个性化的辐射剂量升级。这与我们的机构尤其重要，因为我们将在2010年开设质子治疗机构。我们希望SA 2中研究的NFV（例如肿瘤重新氧化）的阳性结果将在HNC开设新的辅助治疗途径。公共卫生相关性：缺氧已被证明可以限制所有类型的癌症治疗的功效，包括放射线，化学疗法甚至手术（因为低氧肿瘤更有可能侵入和转移）。为了克服这些局限性，至关重要的是能够诊断单个患者肿瘤中缺氧的存在，模式和水平。在PET扫描中，使用缺氧成像剂EF5​​（在组织切片中）和18F-EF5的使用将定义哪些患者以及哪种疗法最有效，以改善患者的预后和生活质量。