MYCN drives a ferroptotic vulnerability in neuroblastoma

MYCN 导致神经母细胞瘤铁死亡的脆弱性

• 批准号: 10736479
• 负责人: Anthony Charles Faber
• 金额: $ 69.67万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736479
• 关键词: Anabolism; Antioxidants; Apoptosis; Apoptotic; Applications Grants; BCL1 Oncogene; BCL2 gene; Biological; Cell Culture Techniques; Cell Death; Cell Line; Cells; Chemicals; Child; Clinic; Clinical; Clinical Investigator; Coenzyme A; Combination Drug Therapy; Combined Modality Therapy; Complex; Cysteine; Dependence; Disease; Drug Metabolic Detoxication; Drug Targeting; FDA approved; Genetic; Genetic Screening; Genomics; Glutathione; Goals; Grant; Growth; Immunotherapy; Iron; MYCN gene; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Modeling; Mus; Nature; Neuroblastoma; Oncogenes; Oncogenic; Oxygen; Pantothenate kinase; Pantothenic Acid; Pathway interactions; Patients; Pediatric Neoplasm; Peroxidases; Pharmacologic Substance; Phenotype; Phosphotransferases; Production; Proliferating; Reaction; Reactive Oxygen Species; Refractory; Relapse; Research Design; Resistance; Selenocysteine; Stress; Testing; Therapeutic; Time; Translating; Translational Research; Work; aged; cancer cell; cancer therapy; combat; disorder risk; experimental study; glutathione peroxidase; high risk; improved; in vivo Model; inhibitor; iron metabolism; kinase inhibitor; mouse model; neuroblastoma cell; new combination therapies; novel; novel therapeutics; patient derived xenograft model; pre-clinical; programs; resistance mechanism; response; screening; selenoprotein; transcription factor; translational medicine; treatment response; tumor

Project Summary: Apoptosis is a type of programmed cell death and has for a long time been appreciated to be a hallmark of cancer cells. In recent years, drugs targeting the apoptotic pathway, such as the FDA- approved BCL-2 inhibitor, venetoclax, have revolutionized therapy in cancers which have a particular vulnerability to targeting this pathway. A different programmed cell death pathway, ferroptosis, has recently been discovered. Understanding which cancers may be vulnerable to the induction of ferroptosis and which targetable molecules are involved could lead to a new wave of successful cancer therapy. MYCN-amplified neuroblastoma (NB) is one of the deadliest subtypes of pediatric cancer. Here in, we demonstrate that amplified MYCN drives an aberrant iron capture program in NB and increases intracellular cysteine biosynthesis and selenocysteine dependence through multiple mechanisms to detoxify reactive oxygen species (ROS) accumulation as a result of high cellular iron. The consequence of these MYCN-directed changes is a synthetic lethality to genetic or pharmaceutical targeting of the glutathione/glutathione peroxidase 4 (GPX4) pathway resulting in ferroptotic cell death. This grant aims to expand our understanding of how MYCN alters cysteine and selenocysteine production and ferroptotic inducing pathways to sustain an antioxidant defense and how these pathways may be exploited pharmaceutically to improve therapeutic responses in this recalcitrant tumor type. Specific Aims: Aim 1: Characterize the ability of MYCN to suppress ferroptosis in neuroblastoma Aim 2: Identification of synthetic lethal ferroptosis resistance mechanisms in MYCN-amplified neuroblastoma Aim 3: In MYCN-amplified neuroblastoma mouse models, evaluate novel ferroptotic combination therapies Study Design: Using well characterized isogenic cell lines and patient-derived xenograft cell cultures, we will mobilize expertise in selenocysteine biosynthesis (Copeland), pantothenate kinase inhibitors (Rock), and genomic screening of ferroptotic pathway modifiers (Olzmann) to better define the ferroptotic vulnerability in MYCN-amplified NB and to uncover novel sensitizers to ferroptotic inducers in MYCN-amplified NB. The goal of these experiments is to not only better understand how the MYCN oncogene hijacks cysteine for selenocysteine production to mount a defense against an oxidized phenotype, but to create new therapeutics to create better anti-ferroptotic approaches in MYCN-amplified NB. To this end, we will work with our preclinical mouse model expert (Koblinski) and a NB clinical investigator (Glod) to build the preclinical evidence of synthetic lethal new therapies into the clinic for refractory NB patients.

项目摘要：细胞凋亡是一种程序性细胞死亡，长期以来一直被认为是 是癌细胞的标志。近年来，针对细胞凋亡途径的药物，如FDA- 批准的bcl2抑制剂ventoclax已经彻底改变了癌症的治疗方法，这种癌症具有特殊的 针对这条路径的脆弱性。一种不同的程序性细胞死亡途径，铁下垂，最近已经 被发现了。了解哪些癌症可能易受铁性下垂的诱导，哪些癌症 靶向分子的参与可能会导致新一轮成功的癌症治疗。MYCN-扩增 神经母细胞瘤(NB)是儿童癌症中最致命的亚型之一。在这里，我们证明了 扩增的MYCN在NB中驱动异常的铁捕获程序并增加细胞内半胱氨酸 生物合成与硒半胱氨酸依赖通过多种机制解毒活性氧 物种(ROS)的积累是高细胞铁的结果。这些MYCN导向后果 改变是对谷胱甘肽/谷胱甘肽过氧化物酶的遗传或药物靶向的合成致死性 4(Gpx4)途径导致铁链细胞死亡。这笔赠款旨在扩大我们对如何 MYCN改变半胱氨酸和硒半胱氨酸的产生和铁链诱导途径以维持AN 抗氧化剂防御以及如何利用这些途径来药物治疗 这种顽固性肿瘤类型的反应。 具体目标： 目的1：研究MYCN对神经母细胞瘤铁性下垂的抑制作用 目的2：在MYCN扩增的神经母细胞瘤中鉴定合成致死性铁下垂抵抗机制 目的3：在MYCN扩增的神经母细胞瘤小鼠模型中，评价新的铁链药物联合疗法 研究设计：使用具有良好特性的等基因细胞系和患者来源的异种移植细胞培养，我们将 调动硒半胱氨酸生物合成方面的专业知识(科普兰)、泛酸激酶抑制剂(ROCK)和 铁上链途径修饰物(Olzmann)的基因组筛选以更好地确定铁上链易感性 MYCN扩增的Nb，并在MYCN扩增的Nb中发现对铁链诱导剂的新型敏化剂。目标是 这些实验不仅是为了更好地了解MYCN癌基因如何劫持半胱氨酸 生产硒半胱氨酸来防御氧化表型，但创造新的治疗方法 为了在MYCN扩增的NB中创造更好的反铁上链方法。为此，我们将与我们的临床前工作 小鼠模型专家(Koblinski)和一名NB临床调查员(Glod)建立临床前证据 用于难治性NB患者的合成致死新疗法进入临床。