Acquired Resistance to Therapy and Iron (ARTI) Center

总体摘要 大约50%的癌症患者接受放射治疗(RT)，但局部复发仍有可能发生 即使使用了先进的RT技术。这种局部复发通常发生在30%-50%的 癌症病例中，RT耐药的获得会加剧这种情况。这种RT阻力尤其适用于 局部晚期胸癌患者，如肺癌和食道癌。RT可以导致一种熨斗- 依赖性细胞死亡方式，称为铁下垂，但铁下垂抵抗是否发生在肿瘤内 上升到获得性RT抵抗是未知的，并且是拟议的获得性抵抗的中心主题 治疗和铁(ARTI)中心。阿尔蒂中心的首要目标是：1)架起基础科学的桥梁 铁下垂在获得性耐药中的机制及其在临床前模型和人类中的翻译研究 患者样本；2)确定最有可能发生获得性RT耐药的患者队列； 以及3)研究新型治疗药物对肺癌和食道癌细胞的再敏化能力。 通过引起铁性下垂进行放射治疗。艺术中心包括两个基本/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将侧重于阐明铁下垂逃避是否是获得性RT的关键驱动因素 利用耐辐射的肺癌和食道癌细胞株和异种移植模型 在项目2中使用。项目2将测试低氧的假设，低氧是长期以来被认为是肿瘤的驱动因素 放射抵抗，抑制RT过程中铁下垂的诱导，并参与RT诱导的获得性抵抗 致上睑下垂。此外，低氧相关基因和其他获得性RT抗性靶点的表达将 在项目3中通过单细胞测序进行分析。项目3调查肿瘤中免疫细胞的变化 化疗放射治疗人源化肿瘤模型的微环境-反应或无反应 有反应性的食管腺癌患者。这些铁下垂介导的免疫学变化 肿瘤微环境可作为判断肿瘤预后的生物标志物 抵抗力和预测癌症患者的预后，这在未来可能会受到铁下垂的调节- 在项目1和2中测试的诱导剂。项目1、2和3将由利用 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 半胱氨酸转运体活性和识别肿瘤内的缺氧区，以及新的氧化还原调节的PET 用于识别激活的先天免疫细胞的示踪剂。艺术中心将开发一个行政核心，用于 ARTI中心项目与核心领导和联合领导之间的有效沟通和协作 与国家癌症研究所(NCI)获得性耐药网络(ARTnet)计划工作人员一起 与其他Artnet中心一样，协同Arti中心的相关活动。

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.