Imaging and Modifying Hypoxia in Head and Neck Squamous Cell Tumors

描述（由申请人提供）：近十年来，缺氧是头颈癌（HNC）治疗抵抗的主要原因这一观察结果已经得到充分证实。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，以确定组织中缺氧的存在，水平和分布。使用的试剂是2-硝基咪唑试剂EF 5，其专门开发为定量缺氧标记物。我们最近已经表明，在HNC中的EF 5的IHC分析对患者结果是预后的。本项目的总体目标是利用18F-EF 5 PET成像来确定作为治疗抵抗因素的缺氧的存在和水平。在我们的第一个特定目标（SA）中，将用18F-EF 5 PET对新发HNC患者进行成像，以确定该信号是否可用作预后和预测标志物。所有患者将接受标准手术方案治疗，然后进行放化疗。手术时采集的组织将用于测定缺氧相关的生物学终点，包括HIF 1？，尿中的增殖（Ki 67）、血管（CD 31）、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的18F-EF 5 PET图像，并评估奈非那韦（NFV），一种临床上用于艾滋病的抗病毒治疗，是否可以改变肿瘤氧水平。这项工作是在PENN辐射生物学实验室发表的观察结果的临床延伸，即NFV是一种辐射致敏剂。将探索与SA 1相似的生物学和患者结局终点。SA 1的长期应用是利用低氧水平和模式进行个体化辐射剂量递增。这在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）的阳性结果将为HNC的辅助治疗开辟新途径。公共卫生相关性：低氧已被证明会限制所有类型的癌症治疗的疗效，包括放射治疗，化疗，甚至手术（因为低氧肿瘤更容易侵入和转移）。为了克服这些局限性，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EF 5（在组织切片中）和18F-EF 5进行PET扫描将确定哪些患者和哪些治疗最有效，以改善患者的预后和生活质量。

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.