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.

总体汇总 大约50%的癌症患者接受放射治疗（RT），但仍可能发生局部复发 即使使用先进的RT技术。这种局部复发，通常发生在30-50%的 在癌症病例中，由于获得RT抗性而恶化。这种RT电阻对于以下情况尤其如此： 局部晚期胸部癌症患者，如肺癌和食管癌。RT可以导致铁- 依赖性细胞死亡模式，称为铁凋亡，但是否铁凋亡抵抗发生在肿瘤内， 获得性RT耐药性的产生尚不清楚，这是拟议的获得性RT耐药性的中心主题。 治疗和铁（阿尔蒂）中心。阿尔蒂中心的总体目标是：1）连接基础科学 获得性耐药性中铁凋亡的机制与临床前模型和人类的转化研究 患者样品; 2）鉴定处于发展获得性RT抗性的最大风险的患者群组; 和3）研究新型治疗剂使肺癌和食道癌细胞重新敏感的能力 通过诱导铁凋亡来辐射。阿尔蒂中心包括两个基本/机械项目（项目1和 项目2）、一个临床前/转化项目（项目3）和一个共享资源核心（分子成像 核心[MIC]）。项目1将重点阐明铁凋亡逃避是否是获得性RT的关键驱动因素 使用放射抗性肺癌和食管癌细胞系和异种移植模型， 在项目2中使用。项目2将测试一个假设，即缺氧，一个长期公认的肿瘤驱动因素， 辐射抗性，抑制RT期间的铁凋亡诱导，并有助于RT诱导的获得性抗性 铁性下垂此外，低氧相关基因和获得性RT抗性的其他靶点的表达将导致低氧相关基因的表达增加。 在项目3中通过单细胞测序进行分析。项目3研究肿瘤中免疫细胞的变化 来源于化放疗反应性或非反应性的人源化肿瘤模型的微环境 反应性食管腺癌患者。这些铁中毒介导的免疫学变化， 肿瘤微环境可以作为预后生物标志物，用于识别可能获得RT的肿瘤 抵抗和预测癌症患者的结果，这可能是，在未来，由铁凋亡调制- 在项目1和2中测试的诱导剂。项目1、2和3将得到多边投资委员会的支持， 生物发光成像监测肿瘤生长，正电子发射断层扫描（PET）示踪剂监测 胱氨酸转运蛋白活性，并确定肿瘤内的缺氧区域，以及新的氧化还原调节PET 用于识别激活的先天免疫细胞的示踪剂。阿尔蒂中心将开发一个管理核心， 阿尔蒂中心项目与核心领导人和联合领导人之间的有效沟通和协作 与国家癌症研究所（NCI）的获得性耐药治疗网络（ARTNet）项目工作人员以及 与其他ARTNet中心一样，协同开展与阿尔蒂中心有关的活动。