Imaging and Modifying Hypoxia in Head and Neck Squamous Cell Tumors

描述（由申请人提供）：缺氧是头颈癌（HNC）治疗耐药的主要原因，这一观察已经确立了近十年。在宾夕法尼亚大学，我们已经开发了侵入性（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。使用的药剂是一种2-硝基咪唑剂EF5，它是专门开发的定量缺氧标志物。我们最近表明，HNC中EF5的免疫组化分析可以预测患者的预后。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阻力因素的存在和水平。在我们的第一个特定目的（SA）中，将对新发HNC患者进行18F-EF5 PET成像，以确定该信号是否可作为预后和预测指标。所有患者都将接受标准的手术治疗，然后进行放化疗。手术中收集的组织将用于测定缺氧相关的生物学终点，包括HIF1？、增殖（Ki67）、血管（CD31）、细胞凋亡、pAkt（辐射抗性）和尿中的骨桥蛋白（OPN）。在我们的第二个SA中，我们将研究复发性HNC的18F-EF5 PET图像，并评估奈非那韦（NFV）是否可以改变肿瘤氧水平，奈非那韦是一种临床使用的艾滋病抗病毒治疗药物。这项工作是宾夕法尼亚大学辐射生物学实验室发表的观察结果的临床延伸，NFV是一种辐射致敏剂。生物学和患者结局终点，类似于SA1，将被探索。SA1的长期应用是利用缺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，因为我们将在2010年开放质子治疗设施。我们希望在SA 2中研究的NFV的积极结果（如肿瘤再氧合）将为HNC的辅助治疗开辟新的途径。公共卫生相关性：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（因为缺氧的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、模式和水平是至关重要的。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些治疗方法最有效，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.