Intra-vital metabolic microscopy to reveal head and neck cancer radiation resistance mechanism in small animal models

活体代谢显微镜揭示小动物模型中的头颈癌辐射抵抗机制

• 批准号: 10119769
• 负责人: Binhua P Zhou
• 金额: $ 30.43万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10119769
• 关键词: Animal Model; Cancer Center; Cancer Patient; Caring; Cells; Cessation of life; Failure; Foundations; Growth Factor; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hypoxia; Immunohistochemistry; In Vitro; Kentucky; Measures; Metabolic; Metabolism; Microscope; Microscopy; Modeling; Optics; Organoids; Patient imaging; Patients; Radiation therapy; Recurrence; Recurrent tumor; Resistance development; Risk; Role; System; Techniques; Technology; Testing; Translating; Tumor-Derived; Universities; Xenograft Model; Xenograft procedure; aerobic glycolysis; angiogenesis; cancer recurrence; hypoxia inducible factor 1; improved; in vivo; in vivo Model; inhibitor/antagonist; metabolomics; outcome forecast; overexpression; portability; prevent; radiation effect; radiation resistance; resistance mechanism; trait; tumor; tumor metabolism; whole body imaging

Most deaths from head and neck squamous cell cancer (HNSCC) result from tumor recurrence following radiotherapy (RT). More than 75% of HNSCC patients receive RT as part of their care and over 50% of them are at risk for developing recurrence post RT. Radio-resistance (RR) leads to poor prognosis in head and neck squamous cell cancer (HNSCC) patients. The failure of RT has been attributed to hypoxia. However, new studies found that RT-induced re-oxygenation rates alone cannot distinguish primary from recurring HNSCC tumors, as some recurrent tumors also showed re-oxygenation after RT. Overexpression of RTinduced Hypoxia-Inducible Factor-1-alpha (HIF-1α) has been shown to be associated with an increased risk of failure of RT. HIF-1α is known to regulate many growth factors to promote aerobic glycolysis and angiogenesis. We hypothesize that RT-induced HIF-1α expression and subsequent alterations in metabolism/vasculature underlie HNSCC RR. Unraveling metabolic traits of cells that evade RT and recur, and the role of the supporting vasculature, is critical to developing strategies to prevent HNSCC recurrence and improve patient survival. However, there are surprisingly few techniques available to provide a systems level view of these hallmarks together in vivo. To fill these gaps, I will build a portable multi-parametric microscope to measure the major axes of metabolism and vasculature in small animal models in vivo. I will then use these platforms to study the effect of radiation on HNSCC tumors and test our hypothesis on HNSCC RR development. This technology fills an important gap between in vitro studies on cells and whole body imaging, and is complementary to metabolomics and immunohistochemistry (IHC). I envision that this system will be well suited to study tumor RR and recurrence in patient-derived xenograft (PDX) and organoid models, which can faithfully recapitulate many micro-environmental features of patient tumors. Successful completion of the proposed studies will set the foundation for translating the optical technology to image patient derived tumor lines in PDX models, allowing us identify predictors of recurrence and develop improved radiotherapeutics (HIF-1 inhibitors) for HNSCC.

大多数头颈鳞状细胞癌 (HNSCC) 死亡是由于放疗 (RT) 后肿瘤复发造成的。超过 75% 的 HNSCC 患者接受放疗作为治疗的一部分，其中超过 50% 的患者面临放疗后复发的风险。放射抗性（RR）导致头颈鳞状细胞癌（HNSCC）患者预后不良。放疗失败的原因是缺氧。然而，新的研究发现放疗引起的。单独的再氧合率无法区分原发性和复发性 HNSCC 肿瘤，因为一些复发性肿瘤在放疗后也表现出再氧合，RT 诱导的缺氧诱导因子 1-α (HIF-1α) 的过度表达已被证明与增加有关。已知 HIF-1α 可以调节许多生长因子以促进有氧糖酵解和血管生成，我们捕获了 RT 诱导的 HIF-1α 表达以及随后的变化。代谢/脉管系统是 HNSCC RR 的基础。揭示逃避 RT 和复发的细胞的代谢特征以及支持脉管系统的作用对于制定预防 HNSCC 复发和提高患者生存的策略至关重要。为了填补这些空白，我将构建一个便携式多参数显微镜来测量体内小动物模型的新陈代谢和脉管系统的主轴。然后使用这些平台来研究辐射对 HNSCC 肿瘤的影响，并检验我们对 HNSCC RR 发展的假设。该技术填补了细胞体外研究和全身成像之间的重要空白，并且是代谢组学和免疫组织化学 (IHC) 的补充。我设想该系统将非常适合研究患者来源的异种移植物（PDX）和类器官模型中的肿瘤RR和复发，这些模型可以忠实地再现患者肿瘤的许多微环境特征，并成功完成。拟议的研究将为将光学技术转化为 PDX 模型中患者来源的肿瘤系成像奠定基础，使我们能够识别复发的预测因子并开发改进的 HNSCC 放射治疗药物（HIF-1 抑制剂）。