Imaging and Modifying Hypoxia in Head and Neck Squamous Cell Tumors

描述(申请人提供)：近十年来，低氧是头颈癌(HNC)治疗抵抗的主要原因的观察已经得到了很好的证实。在宾夕法尼亚大学，我们开发了有创(基于免疫组织化学，IHC)和无创(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，它是专门作为定量缺氧标志物开发的。我们最近已经证明，HNC中EF5的IHC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成像来确定低氧的存在和水平作为治疗耐药因素，以此为基础进行观察。在我们的第一个特定目标(SA)中，将对新生HNC患者进行18F-EF5PET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的手术方案，然后进行化疗和放射治疗。手术中收集的组织将被用来检测与缺氧相关的生物终点，包括HIF1？、增殖(Ki67)、血管(CD31)、细胞凋亡和尿中的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HNC的18F-EF5 PET图像，并评估临床上用于艾滋病的抗病毒治疗Nelfinavir(NFV)是否可以改变肿瘤的氧气水平。这项工作是宾夕法尼亚大学辐射生物学实验室发表的关于NFV是辐射敏感剂的观察结果的临床延伸。将探索类似于SA1的生物学和患者结局终点。SA1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。这与我们的机构特别相关，因为我们将在2010年开设质子治疗设施。我们希望SA2中对NFV(如肿瘤再氧合)的积极结果将为HNC的辅助治疗开辟一条新的途径。与公共健康相关：低氧已被证明限制了所有类型癌症治疗的疗效，包括放疗、化疗，甚至手术(因为低氧肿瘤更有可能侵袭和转移)。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、模式和水平是至关重要的。使用低氧显像剂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将最有效，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.