Project 4: FTO Inhibition to Enhance the Therapeutic Index of Radiotherapy

项目4：FTO抑制提高放疗治疗指数

• 批准号: 10334202
• 负责人: Erinn B. Rankin
• 金额: $ 36.23万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334202
• 关键词: Acute; Adult; Apoptosis; Biological Assay; Bone Marrow; Cancer Cell Growth; Cell Survival; Cells; Cervical; Cervix Neoplasms; Collaborations; Complement; DNA Repair; Data; Failure; Fatty acid glycerol esters; Genetic; Glutamine; Glutathione; Goals; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; In Vitro; Intestines; Kidney; Late Effects; Lung; Malignant Neoplasms; Maps; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Modeling; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Obesity; Oncogenic; Oral mucous membrane structure; Oxidative Stress; Pathway interactions; Patients; Pharmacology; Public Health; RNA; Radiation; Radiation Dose Unit; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radiobiology; Radiosensitization; Renal carcinoma; Research; Role; Safety; Salivary Glands; Signal Transduction; Solid Neoplasm; Supplementation; Testing; Therapeutic; Therapeutic Index; Toxic effect; Treatment Failure; Tumor Tissue; United States National Institutes of Health; alpha ketoglutarate; analytical tool; antitumor effect; base; biological adaptation to stress; cancer cell; effective therapy; epitranscriptomics; gain of function; improved; in vivo; innovation; insight; knock-down; lung cancer cell; metabolomics; mortality; multidisciplinary; mutant; novel; nucleotide metabolism; overexpression; oxidative damage; pre-clinical; radiation response; response; small molecule; stable isotope; standard care; targeted cancer therapy; therapeutic target; therapy outcome; therapy resistant; transcriptome sequencing; tumor; tumor growth; tumor xenograft; uptake

Abstract (Project 4) Radiation therapy is a standard treatment for many solid tumors including cervical, non-small cell lung (NSCLC) cancer, and head and neck cancer. While effective in a large proportion of patients, local failure remains a significant cause of patient morbidity and mortality. An attractive strategy to radiosensitize tumors is targeting cancer-specific glutamine metabolic reprogramming as this pathway supports tumor growth, survival, oxidative stress responses and DNA damage repair. The RNA demethylase FTO is emerging as a therapeutic target for cancer therapy as it is overexpressed and oncogenic in several cancers including cervical, non-small cell lung cancer (NSCLC), and head and neck cancers. However, FTO has not previously been explored as a target for tumor radiosensitization. Preliminary studies demonstrate that FTO inhibition reduces tumor growth and survival in vitro and in vivo. At the molecular level, FTO inhibition reduces SLC1A5 expression and glutamine uptake in cancer cells. Importantly, FTO inhibition radiosensitizes cervical and KEAP1 mutant NSCLC cancer cells. This proposal will test the hypothesis that inhibition the RNA demethylase fat-mass and obesity-associated (FTO) will enhance the therapeutic index of radiotherapy in solid tumors through the inhibition of glutamine metabolism. Aim 1 will determine the anti-tumor effects of FTO inhibition in combination with radiation on a range of solid tumors cancers using genetic and pharmacologic approaches. Aim 2 determine if FTO inhibition enhances the radiation response in cancer cells by reducing glutamine metabolism, oxidative stress and/or DNA damage repair responses using knockdown and gain of function approaches. Aim 3 will test the hypothesis that FTO inhibition will not impact the radiation sensitivity of normal tissues that develop radiation- induced toxicity when treating cervical, NSCLC and HNSCC tumors. The acute and late effects of FTO inhibition on the radiation response in the bone marrow, intestine (collaboration with Project 1), salivary gland and oral mucosa (collaboration with Project 2), and lung (collaboration with Project 3) will be analyzed using models of global conditional FTO inactivation in adult mice. Together with Projects 1, 2 and 3 this project will investigate the role of FTO in both the tumor and normal tissue radiation response with the goal of ascertaining the therapeutic potential of FTO-based radiosensitizers. In addition to determining the tumor types that can be effectively and safely treated with FTO inhibition, they will use cutting edge analytical tools to study the mechanism of action. Successful completion of these aims will 1) identify FTO is an epitranscriptomic regulator of cancer cell glutamine metabolism and oxidative stress; 2) provide the preclinical data to support FTO as a safe and effective molecular target to radiosensitize tumors; 3) provide proof of concept studies to demonstrate that small molecule targeting of FTO demethylase activity can radiosensitize tumors.

摘要（项目 4） 放射治疗是许多实体瘤的标准治疗方法，包括宫颈癌、非小细胞肺癌 (NSCLC) 癌症和头颈癌。虽然对大部分患者有效，但局部失败仍然是一个问题 患者发病和死亡的重要原因。一种有吸引力的肿瘤放射增敏策略是靶向 癌症特异性谷氨酰胺代谢重编程，因为该途径支持肿瘤生长、存活、氧化 应激反应和 DNA 损伤修复。 RNA 去甲基化酶 FTO 正在成为以下疾病的治疗靶点： 癌症治疗，因为它在包括宫颈癌、非小细胞肺癌在内的多种癌症中过度表达并具有致癌性 癌症（NSCLC）和头颈癌。然而，FTO 此前并未被探索作为目标 肿瘤放射增敏。初步研究表明 FTO 抑制可降低肿瘤生长和存活 体外和体内。在分子水平上，FTO 抑制可降低 SLC1A5 的表达和谷氨酰胺的摄取 癌细胞。重要的是，FTO 抑制可使宫颈癌细胞和 KEAP1 突变 NSCLC 癌细胞放射增敏。这 该提案将检验抑制 RNA 去甲基酶脂肪量和肥胖相关的假设 （FTO）将通过抑制以下物质来提高实体瘤放射治疗的治疗指数： 谷氨酰胺代谢。目标 1 将确定 FTO 抑制与 使用遗传和药理学方法对一系列实体瘤癌症进行放射治疗。目标 2 确定是否 FTO 抑制通过减少谷氨酰胺代谢、氧化增强癌细胞的放射反应 使用击倒和功能获得方法修复应激和/或 DNA 损伤反应。目标 3 将进行测试 假设 FTO 抑制不会影响产生辐射的正常组织的辐射敏感性 在治疗宫颈癌、非小细胞肺癌和头颈部鳞癌时会引起毒性。 FTO 抑制的急性和迟发效应 关于骨髓、肠道（与项目 1 合作）、唾液腺和口腔的辐射反应 粘膜（与项目 2 合作）和肺（与项目 3 合作）将使用以下模型进行分析 成年小鼠的全局条件性 FTO 失活。该项目将与项目 1、2 和 3 一起进行调查 FTO 在肿瘤和正常组织放射反应中的作用，目的是确定 基于 FTO 的放射增敏剂的治疗潜力。除了确定肿瘤类型外， 通过 FTO 抑制有效且安全地进行治疗，他们将使用尖端的分析工具来研究 作用机制。成功完成这些目标将 1) 确定 FTO 是表观转录组调控因子 癌细胞谷氨酰胺代谢和氧化应激； 2）提供临床前数据支持FTO作为 安全有效的放射增敏肿瘤分子靶点； 3）提供概念研究证明 靶向 FTO 去甲基酶活性的小分子可以使肿瘤放射增敏。