Administrative Supplement: Metabolic Alterations Associated with Acquired Resistance to Ferroptosis in Esophageal Cancer

行政补充：与食管癌铁死亡获得性抗性相关的代谢改变

• 批准号: 10830901
• 负责人: Boyi Gan
• 金额: $ 18.23万
• 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/10830901
• 关键词: Achievement; Administrative Supplement; Advisory Committees; Basic Science; Cancer Center; Cancer Patient; Cancer cell line; Cell Death; Cell Death Induction; Cells; Clinical; Clinical Trials; Cloning; Collaborations; Communication; Cystine; Data; Development; Drug resistance; Esophageal Adenocarcinoma; Failure; Family; Feedback; Fostering; Foundations; Future; Genes; Genomics; Goals; Grant; Guidelines; Human; Hypoxia; Hypoxia Inducible Factor; Image; Imaging Device; Immune; Immunologics; Immunotherapy; Infrastructure; Iron; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Malignant neoplasm of thorax; Mediating; Medical; Metabolic; Modality; Modeling; Monitor; Mus; National Cancer Institute; Nature; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Patient-Focused Outcomes; Patients; Play; Policies; Positron-Emission Tomography; Pre-Clinical Model; Production; Prognostic Marker; Radiation; Radiation Oncology; Radiation therapy; Radiation-Sensitizing Agents; Reagent; Recurrence; Recurrent disease; Reporter Genes; Research; Research Project Grants; Resistance; Resource Sharing; Resources; Risk; Role; Sampling; Techniques; Testing; Therapeutic; Therapeutic Agents; Tracer; Transfection; Transgenic Organisms; Translating; Translational Research; Tumor Suppression; University of Texas M D Anderson Cancer Center; Xenograft Model; activating transcription factor 4; bioluminescence imaging; cancer cell; cancer imaging; cancer therapy; cancer type; chemoradiation; clinically significant; cohort; determinants of treatment resistance; drug sensitivity; effective therapy; hormone therapy; imaging program; improved; individual patient; member; molecular imaging; multidisciplinary; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; programs; radiation resistance; radioresistant; single cell sequencing; solute; stable cell line; synergism; targeted treatment; therapy resistant; treatment strategy; tumor; tumor growth; tumor hypoxia; tumor microenvironment

Overall Summary Approximately 50% of cancer patients are treated with radiation therapy (RT), but local recurrence can still occur even with the use of advanced RT techniques. This local recurrence, which commonly develops in 30-50% of cancer cases, is exacerbated by the acquisition of RT resistance. This RT resistance is especially true for patients with locally advanced thoracic cancers, such as lung and esophageal cancers. RT can lead to an iron- dependent cell death modality, called ferroptosis, but whether ferroptosis resistance occurs within tumors giving rise to acquired RT resistance is not known and is the central theme of the proposed Acquired Resistance to Therapy and Iron (ARTI) Center. The overarching goals of the ARTI Center are: 1) to bridge the basic science mechanisms of ferroptosis in acquired resistance with translational research in preclinical models and human patient samples; 2) to identify cohorts of patients who are at greatest risk to develop acquired RT resistance; and 3) to investigate the ability of novel therapeutic agents to re-sensitize lung and esophageal cancer cells to radiation by inducing ferroptosis. The ARTI Center comprises two basic/mechanistic projects (Project 1 and Project 2), one preclinical/translational project (Project 3), and one shared resource core (Molecular Imaging Core [MIC]). Project 1 will focus on elucidating whether ferroptosis evasion is a key driver in acquired RT resistance using radioresistant lung cancer and esophageal cancer cell lines and xenograft models that will be used in Project 2. Project 2 will test the hypothesis that hypoxia, a long-recognized driver of tumor radioresistance, suppresses ferroptosis induction during RT and contributes to RT-induced acquired resistance to ferroptosis. Furthermore, expression of hypoxia-related genes and other targets of acquired RT resistance will be analyzed by single-cell sequencing in Project 3. Project 3 investigates changes in immune cells in the tumor microenvironment of humanized tumor models derived from chemoradiation therapy-responsive or -non- responsive esophageal adenocarcinoma patients. These ferroptosis-mediated immunologic changes in the tumor microenvironment may serve as prognostic biomarkers for identifying tumors that may acquire RT resistance and predicting cancer patient outcomes, which could, in the future, be modulated by the ferroptosis- inducing agents tested in Projects 1 and 2. Projects 1, 2, and 3 will be supported by the MIC that utilizes bioluminescence imaging to monitor tumor growth, positron emission tomography (PET) tracers to monitor cystine transporter activity and to identify hypoxic regions within tumors, as well as novel, redox-tuned PET tracers for identifying activated innate immune cells. The ARTI Center will develop an Administrative Core for effective communication and collaboration between the ARTI Center Project and Core Leaders and Co-Leaders with National Cancer Institute (NCI) of Acquired Resistance to Therapy Network (ARTNet) program staff as well as other ARTNet centers to synergize ARTI Center-related activities.

总结 大约50％的癌症患者接受放射疗法（RT）治疗，但仍可能发生局部复发 即使使用高级RT技术。这种局部复发，通常在30-50％ 癌症病例因获得RT耐药性而加剧。这种RT抵抗尤其如此 患有局部晚期胸腔癌的患者，例如肺癌和食道癌。 RT会导致铁 依赖的细胞死亡方式，称为铁铁作用，但是肿瘤中是否发生了耐铁的耐药性 提高到获得的RT阻力尚不清楚，这是拟议获得的抵抗的核心主题 治疗和铁（ARTI）中心。 ARTI中心的总体目标是：1）桥接基础科学 临床前模型和人类的转化研究中获得的耐药性的铁凋亡机制 病人样本； 2）确定有最大风险的患者的同伙； 3）研究新型治疗剂将肺和食管癌细胞重新敏感的能力 通过诱导铁铁作用来辐射。 ARTI中心包括两个基本/机械项目（项目1和 项目2），一个临床前/翻译项目（项目3）和一个共享资源核心（分子成像 核心[麦克风]）。项目1将重点阐明逃避弹药是被收购的RT的关键驱动力 使用辐射抗肺癌和食管癌细胞系和异种移植模型的耐药性 在项目2中使用。项目2将检验以下假设：缺氧是肿瘤的长期认可的驱动因素 放射线抗性，抑制RT期间的铁铁作用，并导致RT诱导的抗性 用于铁铁。此外，缺氧相关基因的表达和获得的RT电阻的其他靶标 通过项目3中的单细胞测序进行分析。项目3研究了肿瘤中免疫细胞的变化 源自化学放疗反应性或-non-的人性化肿瘤模型的微环境 反应性食管腺癌患者。这些铁铁毒性介导的免疫学变化 肿瘤微环境可以用作预后的生物标志物，用于鉴定可能获得RT的肿瘤 抗药性和预测癌症患者的结局，这将来可能会受到铁铁毒性的调节 在项目1和2。项目1、2和3中测试的诱导代理将得到利用的麦克风的支持 生物发光成像以监测肿瘤生长，正电子发射断层扫描（PET）示踪剂以监测 胱氨酸转运蛋白活性并确定肿瘤内的低氧区域以及新型的氧化还原pet 用于识别活化的先天免疫细胞的示踪剂。 ARTI中心将为 ARTI中心项目与核心领导者和共同领导者之间的有效沟通和协作 与国家癌症研究所（NCI）一起获得了对治疗网络（ARTNET）计划人员的抵抗力 正如其他Artnet中心以协同ARTI中心相关的活动。