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.

总体总结 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% 的患者中 癌症病例中，RT 耐药性的获得会加剧这种情况。这种 RT 电阻尤其适用于 患有局部晚期胸部癌症（例如肺癌和食道癌）的患者。 RT 可导致铁 依赖性细胞死亡方式，称为铁死亡，但肿瘤内是否发生铁死亡抵抗 获得性 RT 耐药性的上升尚不清楚，这是拟议的获得性 RT 耐药性的中心主题 治疗和铁 (ARTI) 中心。 ARTI 中心的总体目标是： 1) 架起基础科学的桥梁 获得性耐药中铁死亡的机制以及临床前模型和人类的转化研究 患者样本； 2) 确定最有可能发生获得性 RT 耐药的患者群体； 3) 研究新型治疗药物使肺癌和食道癌细胞重新敏感的能力 辐射通过诱导铁死亡。 ARTI 中心包括两个基本/机械项目（项目 1 和 项目 2）、1 个临床前/转化项目（项目 3）和 1 个共享资源核心（分子成像 核心[MIC]）。项目 1 将重点阐明铁死亡逃避是否是获得性 RT 的关键驱动因素 使用抗辐射肺癌和食管癌细胞系和异种移植模型来确定耐药性 用于项目 2。项目 2 将检验以下假设：缺氧是长期以来公认的肿瘤驱动因素 放射抗性，抑制放疗期间铁死亡的诱导，并有助于放疗诱导的获得性抗性 至铁死亡。此外，缺氧相关基因和获得性 RT 抗性的其他靶标的表达将 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 源于放化疗反应或非反应的人源化肿瘤模型的微环境 反应性食管腺癌患者。这些铁死亡介导的免疫学变化 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 抵抗力并预测癌症患者的结果，这在未来可能会受到铁死亡的调节 诱导剂在项目 1 和 2 中进行了测试。项目 1、2 和 3 将得到 MIC 的支持，该项目利用 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识别肿瘤内的缺氧区域，以及新型氧化还原调谐 PET 用于识别激活的先天免疫细胞的示踪剂。 ARTI 中心将开发一个行政核心 ARTI中心项目与核心领导者和联合领导者之间的有效沟通与协作 以及美国国家癌症研究所 (NCI) 获得性治疗耐药网络 (ARTNet) 项目的工作人员 与其他 ARTNet 中心一样，协同 ARTI 中心相关活动。