MYCN drives a ferroptotic vulnerability in neuroblastoma

MYCN 导致神经母细胞瘤铁死亡的脆弱性

基本信息

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
项目类别：
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

项目摘要

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：凋亡是一种程序性细胞死亡的一种，很长一段时间都值得注意成为癌细胞的标志。近年来，针对凋亡途径的药物，例如FDA- 批准的Bcl-2抑制剂Venetoclax已彻底改变了具有特定的癌症的癌症针对此途径的脆弱性。不同的程序性细胞死亡途径，铁凋亡，最近有被发现。了解哪种癌症可能容易受到诱导性铁毒性的攻击以及哪些癌症涉及可靶向的分子可能会导致成功的癌症治疗。 mycn放大神经母细胞瘤（NB）是小儿癌最致命的亚型之一。在这里，我们证明了放大MYCN在NB中驱动了异常的铁捕获程序，并增加了细胞内半胱氨酸生物合成和硒代半半胱氨酸的依赖性通过多种机制排毒活性氧高细胞铁的结果（ROS）积累。这些MYCN导向的结果变化是谷胱甘肽/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）途径导致铁毒细胞死亡。该赠款旨在扩大我们对如何的理解 MYCN改变了半胱氨酸和硒代半胱氨酸的产生以及诱导的诱导途径抗氧化剂防御以及如何利用这些途径来改善治疗性这种顽固性肿瘤类型的反应。具体目的： AIM 1：表征MYCN抑制神经母细胞瘤的肥大的能力 AIM 2：鉴定MyCN放大神经母细胞瘤中的合成致死性铁毒性抗性机制 AIM 3：在MyCN放大的神经母细胞瘤小鼠模型中，评估新型的铁氧组合疗法研究设计：使用良好特征的等源细胞系和患者来源的异种移植细胞培养物，我们将动员硒代半胱氨酸生物合成（Copeland），泛素激酶抑制剂（岩石）和铁毒通路修饰符（OLZMANN）的基因组筛查更好地定义了铁毒性脆弱性 MYCN放大NB，并发现了对MyCN放大NB中的铁毒剂诱导剂的新型敏化剂。目标这些实验不仅是更好地了解Mycn Oncogene劫持半胱氨酸的方式硒代半胱氨酸生产以防止氧化表型，但要创建新的治疗剂在MYCN放大的NB中创建更好的抗肿瘤方法。为此，我们将与我们的临床前合作小鼠模型专家（Koblinski）和NB临床研究者（GLOD），以建立临床前证据为难治性NB患者诊所的合成致命疗法。