Tumor hypoxia promotes acquired resistance to radiation through ferroptosis inhibition

肿瘤缺氧通过抑制铁死亡促进获得性放射抵抗

• 批准号: 10517144
• 负责人: Dadi Jiang
• 金额: $ 31.13万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517144
• 关键词: 3-Dimensional; Anabolism; Anatomy; Area; Basic Science; Cancer cell line; Cause of Death; Cell Culture Techniques; Cell Death; Cell physiology; Clinical; Combined Modality Therapy; Cystine; DNA Damage; Data; Disease; Environment; Esophageal Adenocarcinoma; Esophageal Neoplasms; FDA approved; Family; Genes; Genetic; Genetic Transcription; Glutathione; Goals; Hyperbaric Oxygen; Hyperbaric Oxygenation; Hypoxia; Hypoxia Inducible Factor; In Vitro; Investigation; Ionizing radiation; Iron; Lipid Peroxidation; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Measures; Mediating; Mediator of activation protein; Monitor; Mus; Neoplasm Metastasis; Organoids; Oxygen; Pathway interactions; Patient Selection; Pharmacology; Play; Positron-Emission Tomography; Proliferating; Radiation; Radiation Tolerance; Radiation induced damage; Radiation therapy; Regulation; Resistance; Role; Signal Pathway; Site; Solid; Testing; Therapeutic; Time; Tracer; Tumor Oxygenation; Up-Regulation; Vascular blood supply; acquired factor; activating transcription factor; activating transcription factor 4; bHLH-PAS factor HLF; biological adaptation to stress; bioluminescence imaging; cancer cell; cancer therapy; cancer type; cell type; chemoradiation; design; epithelial to mesenchymal transition; hypoxia inducible factor 1; in vivo; inhibitor; ionization; member; molecular imaging; neoplastic cell; pre-clinical; radiation resistance; response; small molecule; small molecule inhibitor; solute; therapeutically effective; therapy resistant; transcription factor; tumor; tumor growth; tumor hypoxia; tumor metabolism; tumor microenvironment; tumor xenograft

Project 2 Summary Tumor hypoxia, defined as low intratumoral oxygen tension, is common to most solid malignancies, including lung and esophageal cancer. Lung and esophageal cancer treatments include radiation therapy (RT); however, clinically, these cancers develop acquired resistance to RT. The mechanisms of acquired resistance to RT are unknown but may involve a type of cell death called ferroptosis, which is the overarching theme of the proposed Acquired Resistance to Therapy and Iron (ARTI) Center. Project 2 will contribute to this overarching theme by determining whether hypoxia drives ferroptosis resistance, thereby promoting the acquired resistance to RT. Project 2 will utilize lung and esophageal cancer cell lines generated in Project 1 that are deficient in the ferroptosis resistance-mediator Solute Carrier Family 7 Member 11 (SLC7A11) and one of its transcription factors: activating transcription factor 4 (ATF4). The transcription of genes, including hypoxia-related genes, may be dynamically regulated within tumor cells and cells of the tumor microenvironment during chemoradiation therapy (CRT) of esophageal adenocarcinoma, which is a focus of Project 3. In order to determine whether oxygen is required for ferroptosis induction by RT, lung and esophageal cancer cells will be subjected to varying oxygen concentrations and radiosensitivity, lipid peroxidation (i.e., driver of ferroptosis), and SLC7A11 expression will be measured (Aim 1). Aim 2 will focus on the delineation of the mechanisms of hypoxia-driven ferroptosis resistance during acquired RT resistance by determining whether SLC7A11 expression is dependent on ATF4 under hypoxic conditions during RT. Furthermore, as hypoxia inducible factors (HIFs) have been shown to promote radioresistance, the effect of hypoxia-induced HIF activation in acquired resistance to ferroptosis will be investigated. To test the hypothesis that enhanced tumor oxygenation through hyperbaric oxygen treatment (HBOT) as well as small molecule HIF and ATF4 inhibitors can overcome acquired radioresistance by enhancing ferroptosis induction, lung tumor and esophageal tumor xenografts in mice will be treated with RT in combination with HBOT or HIF/ATF4inhibitors(Aim 3). Tumor growth after RT will be monitored with weekly noninvasive bioluminescence imaging at the Molecular Imaging Core (MIC). Furthermore, in the MIC, hypoxic regions within tumors will be monitored in real-time by performing positron emission tomography (PET) using the PET tracer 18F-Fluoroazomycin arabinoside (FAZA). Overall, the differential regulation of ferroptosis and acquired RT resistance by poorly oxygenated and well oxygenated areas in tumors discovered in Project 2 will iteratively strengthen and support the basic science/mechanistic Project 1 and the preclinical/translational Project 3 by helping identify tumor regions that may develop acquired resistance to RT that could aid in patient selection for subsequent treatments.

项目2摘要 肿瘤缺氧，定义为肿瘤内低氧分压，常见于大多数实体恶性肿瘤，包括 肺癌和食道癌。肺癌和食管癌的治疗包括放射治疗（RT）;然而， 在临床上，这些癌症发展出对RT的获得性抗性。 未知，但可能涉及一种称为铁凋亡的细胞死亡，这是拟议的首要主题。 获得性抗铁治疗（阿尔蒂）中心。项目2将促进这一总体主题 通过确定缺氧是否驱动铁凋亡抗性，从而促进对RT的获得性抗性。 项目2将利用项目1中产生的肺癌和食管癌细胞系，这些细胞系缺乏 铁凋亡抗性介体溶质载体家族7成员11（SLC 7A 11）及其转录产物之一 转录激活因子4（ATF 4）。基因的转录，包括缺氧相关基因，可能 在放化疗期间在肿瘤细胞和肿瘤微环境的细胞内被动态调节 食管腺癌的CRT治疗，这是项目3的重点。为了确定是否 由于RT诱导的铁凋亡需要氧，因此肺癌和食管癌细胞将受到不同的 氧浓度和放射敏感性，脂质过氧化（即，铁凋亡的驱动因素）和SLC 7A 11 将测量表达（目标1）。目的2将重点阐述缺氧驱动的机制， 通过确定SLC 7A 11表达是否依赖于获得性RT抵抗期间的铁凋亡抵抗 此外，作为缺氧诱导因子（HIF），已经显示， 为了促进辐射抗性，低氧诱导的HIF激活在获得性抗铁凋亡中的作用将 追究为了验证通过高压氧治疗增强肿瘤氧合的假设， （HBOT）以及小分子HIF和ATF 4抑制剂可以通过增强获得性辐射抗性来克服获得性辐射抗性。 小鼠中的铁凋亡诱导、肺肿瘤和食管肿瘤异种移植物将用RT组合治疗 HBOT或HIF/ATF 4抑制剂（Aim 3）。RT后的肿瘤生长将通过每周一次的无创性检查进行监测。 生物发光成像在分子成像核心（MIC）。此外，在MIC中， 通过使用PET示踪剂进行正电子发射断层扫描（PET）， 18F-氟唑霉素阿拉伯糖苷（FAZA）。总的来说，铁凋亡和获得性RT的差异调节 在项目2中发现的肿瘤中氧合不良和氧合良好区域的耐药性将迭代 加强和支持基础科学/机制项目1和临床前/转化项目3， 帮助识别可能对RT产生获得性耐药性的肿瘤区域， 后续治疗。