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.

整体总结