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.

放射治疗（RT）后肿瘤复发导致头颈鳞状细胞癌（HNSCC）大多数死亡。作为护理的一部分，超过75％的HNSCC患者接受了RT，其中超过50％的患者有患RT后复发的风险。放射性耐药性（RR）导致头颈鳞状细胞癌（HNSCC）患者的预后不良。 RT的失败归因于缺氧。然而，新的研究发现，仅RT诱导的重新氧化速率不能将原发性与复发性HNSCC肿瘤区分开，因为某些复发性肿瘤还显示了RT后的重新氧肿瘤。 RT诱导的低氧诱导因子-1-Alpha（HIF-1α）的过表达已证明与RT失败的风险增加有关。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。我们假设RT诱导的HIF-1α表达和随后的新陈代谢/脉管系统的改变是HNSCC RR。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防止HNSCC复发并改善患者生存的策略至关重要。但是，令人惊讶的是，很少有技术可以在体内一起提供这些标志的系统级别。为了填补这些空白，我将建立一个便携式多参数显微镜，以测量体内小动物模型中的代谢和脉管系统的主要轴。然后，我将使用这些平台研究辐射对HNSCC肿瘤的影响，并测试我们对HNSCC RR开发的假设。这项技术填补了对细胞和全身成像的体外研究之间的重要空白，并且与代谢组学和免疫组织化学（IHC）相辅相成。我设想该系统将非常适合研究患者衍生的Xenographic（PDX）和类器官模型的肿瘤RR和复发，这些模型可以忠实地概括患者肿瘤的许多微环境特征。拟议研究的成功完成将为将光学技术转换为PDX模型中的患者衍生肿瘤系的基础，从而使我们确定复发的预测因子，并为HNSCC开发了改进的放射治疗药（HIF-1抑制剂）。