Targeting EGFR/FOXG1-mediated resistance to ONC201 in H3K27M-mutant diffuse midline glioma

在 H3K27M 突变的弥漫性中线神经胶质瘤中靶向 EGFR/FOXG1 介导的 ONC201 耐药性

基本信息

批准号：
10556344
负责人：
Carl J Koschmann
金额：
$ 39.61万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556344
关键词：
Adult Agonist Apoptosis Binding Bioenergetics Brain Brain Stem Breast Cancer Cell Cell Death Cells Child Clinical Clinical Data Combined Modality Therapy DNA Binding DRD2 gene Data Databases Development Dopamine D2 Receptor Dopamine Receptor EGFR inhibition Epidermal Growth Factor Receptor FOXG1B gene Genes Genetic Genetic Transcription Genomics Glioma Glycolysis H3 K27M mutation Histones Human Immunohistochemistry In Vitro Induction of Apoptosis International Location Malignant Neoplasms Mediating Metabolic Pathway Mitochondria Modeling Molecular Mus Mutation Outcome Oxidative Phosphorylation Pathway interactions Patients Peptide Hydrolases Phase Phenotype Progression-Free Survivals Radiation Reporting Research Resistance Role Signal Transduction Site Stains Stress Subgroup TNF-related apoptosis-inducing ligand Thalamic structure Therapeutic Translations Work antagonist cancer cell cell type clinical efficacy clinical predictors combinatorial diffuse midline glioma glioma cell line improved in vivo knock-down neoplastic cell nerve stem cell patient population response transcription factor tumor young adult

项目摘要

PROJECT SUMMARY / ABSTRACT Background and long-term objectives: Children and young adults with diffuse midline glioma (DMG) harboring H3K27M mutation rarely survive longer than two years and have no proven therapies beyond radiation. The dopamine receptor DRD2 antagonist ONC201 induces transcription of TNF-related apoptosis- inducing ligand (TRAIL), leading to apoptosis in multiple tumor cell types. ONC201 additionally binds and activates the mitochondrial protease ClpP, resulting in mitochondrial-mediated cell death in breast cancer cells with active oxidative phosphorylation (OXPHOS). ONC201 is in early phase use in H3K27M-DMG, but its mechanism and efficacy remains unknown. In our preliminary data, ONC201 is effective in murine H3 K27M- mutant gliomas. In our unpublished clinical data (n=50 H3K27M patients), ONC201 doubles PFS and overall survival (OS) in some clinical sub-groups (e.g. thalamic H3K27M) with multiple sustained responses. Despite this impressive efficacy in H3K27M-DMG, we do not know how ONC201 works in H3K27M-DMG tumor cells or how to improve responses in resistant tumors. In analysis of tumor sequencing, ONC201 resistance correlates with high expression of EGFR and the brain developmental transcription factor FOXG1. FOXG1 expression is also the strongest negative predictor of ONC201 sensitivity in human glioma cell lines. In order to prioritize which patients should be treated with ONC201 and to generate rationale combination therapies, there is a critical need to elucidate the mechanism of ONC201 sensitivity in H3K27M cells. Our central hypothesis is that ONC201 is effective in H3K27M-DMG tumors with active OXPHOS through targeting of ClpP and that EGFR signaling mediates ONC201 resistance by inactivating OXPHOS via FOXG1. This is based on our preliminary data in K27M-DMG cells, which shows that cells cultured in media that promotes OXPHOS have an improved response to ONC201, and (iii) EGFR knockdown reduces FOXG1 genomic binding and improves ONC201 response. Approach: In Specific Aim 1, we will determine the impact of: (i) ClpP mitochondrial targeting vs. DRD2 antagonism and (ii) glycolysis vs OXPHOS, in the sensitivity of H3K27M-DMG cells to ONC201. In Specific Aim 2, we will determine the role of FOXG1 in H3K27M-DMG bioenergetics. In Specific Aim 3, we will determine the ability of EGFR inhibition to impact ONC201-induced mitochondrial stress in H3K27M-DMG and for baseline EGFR/FOXG1 tumor staining to predict ONC201 response. We expect to define the mechanism by which EGFR and FOXG1 impact mitochondrial bioenergetics and ONC201 sensitivity in H3K27M-DMG tumors. Significance: This contribution is expected to be significant because it will allow clinicians to prioritize which H3K27M-DMG patients should be treated with ONC201 and provide a platform for rationale combinatorial treatments to improve ONC201 resistance. Our translational team will soon open a multi-site international platform trial that can implement the results of this proposal immediately for patients with H3K27M-DMG.

项目概要/摘要背景和长期目标：患有弥漫性中线胶质瘤 (DMG) 的儿童和年轻人携带 H3K27M 突变的患者很少能存活超过两年，并且没有经过证实的治疗方法辐射。多巴胺受体 DRD2 拮抗剂 ONC201 诱导 TNF 相关细胞凋亡的转录诱导配体（TRAIL），导致多种肿瘤细胞类型凋亡。 ONC201还结合激活线粒体蛋白酶 ClpP，导致乳腺癌细胞中线粒体介导的细胞死亡具有活性氧化磷酸化（OXPHOS）。 ONC201 正处于 H3K27M-DMG 的早期使用阶段，但其机制和功效仍不清楚。根据我们的初步数据，ONC201 对鼠 H3 K27M 有效- 突变神经胶质瘤。在我们未发表的临床数据中（n=50 名 H3K27M 患者），ONC201 使 PFS 和总体 PFS 翻倍某些临床亚组（例如丘脑 H3K27M）的生存率 (OS) 具有多种持续反应。尽管 H3K27M-DMG 中的这种令人印象深刻的功效，我们不知道 ONC201 如何在 H3K27M-DMG 肿瘤细胞中发挥作用，或者如何提高耐药肿瘤的反应。在肿瘤测序分析中，ONC201 耐药性与 EGFR 的高表达以及脑发育转录因子 FOXG1。 FOXG1 表达也是最强的阴性预测因子人神经胶质瘤细胞系中的 ONC201 敏感性。为了优先考虑哪些患者应该接受治疗 ONC201并产生合理的联合疗法，迫切需要阐明其机制 H3K27M 细胞中 ONC201 的敏感性。我们的中心假设是 ONC201 对 H3K27M-DMG 有效通过靶向 ClpP 具有活性 OXPHOS 的肿瘤以及 EGFR 信号传导介导 ONC201 耐药性通过 FOXG1 灭活 OXPHOS。这是基于我们在 K27M-DMG 细胞中的初步数据，该数据显示在促进 OXPHOS 的培养基中培养的细胞对 ONC201 和 (iii) EGFR 的反应有所改善敲低可减少 FOXG1 基因组结合并改善 ONC201 反应。方法：在具体目标 1 中，我们将确定以下因素的影响：(i) ClpP 线粒体靶向与 DRD2 H3K27M-DMG 细胞对 ONC201 的敏感性中的拮抗作用和 (ii) 糖酵解与 OXPHOS 的关系。特定目标 2，我们将确定FOXG1在H3K27M-DMG生物能学中的作用。在具体目标 3 中，我们将确定 EGFR 抑制影响 H3K27M-DMG 中 ONC201 诱导的线粒体应激和基线的能力 EGFR/FOXG1 肿瘤染色可预测 ONC201 反应。我们期望定义 EGFR 的机制 FOXG1 影响 H3K27M-DMG 肿瘤中的线粒体生物能学和 ONC201 敏感性。意义：这一贡献预计将非常重要，因为它将允许临床医生优先考虑哪些 H3K27M-DMG 患者应接受 ONC201 治疗，并为合理组合提供平台治疗以提高 ONC201 耐药性。我们的翻译团队很快将开设一个多站点国际平台试验可以立即对 H3K27M-DMG 患者实施该提案的结果。