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

• 批准号: 10337525
• 负责人: Carl J Koschmann
• 金额: $ 43.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 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/10337525
• 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; 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; base; 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

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 In our unpublished clinical data (n=50 H3K27M patients), ONC201 doubles PFS and overall survival (OS) in some clinical sub-groups (e.g. thalamic H3K27M) with multiple sustained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.

项目摘要/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突变的人很少能存活超过两年，而且没有经过验证的治疗方法 辐射。多巴胺受体DRD2拮抗剂ONC201诱导肿瘤坏死因子相关细胞凋亡转录 诱导配体(TRAIL)，导致多种肿瘤细胞类型的凋亡。ONC201额外绑定和 激活线粒体蛋白水解酶ClpP，导致乳腺癌细胞线粒体介导的细胞死亡 活性氧化磷酸化(OXPHOS)。ONC201在H3K27M-DMG中处于早期使用阶段，但其 其作用机制和疗效尚不清楚。在我们的初步数据中，ONC201对小鼠H3 K27M- 突变型胶质瘤。在我们未发表的临床数据中(n=50名H3K27M患者)，ONC201使PFS和总体 一些临床亚组(如丘脑H3K27M)的存活率(OS)具有多个持续反应。尽管 在H3K27M-DMG中的这种令人印象深刻的疗效，我们不知道ONC201在H3K27M-DMG肿瘤细胞或 如何改善耐药肿瘤的反应。 在肿瘤测序分析中，ONC201耐药与EGFR的高表达和 脑发育转录因子FOXG1。FOXG1的表达也是最强的负面预测因子 人脑胶质瘤细胞系对ONC201的敏感性。为了确定哪些患者应该接受优先治疗 ONC201和产生联合治疗的理论基础，迫切需要阐明其机制 H3K27M细胞对ONC201的敏感性。我们的中心假设是ONC201在H3K27M-DMG中有效 靶向ClpP和EGFR信号通路介导ONC201耐药的OXPHOS活性肿瘤 通过FOXG1使OXPHOS失活。这是基于我们在K27M-DMG细胞中的初步数据，这表明 在促进OXPHOS的培养液中培养的细胞对ONC201的反应更好，以及(Iii)EGFR 基因敲除减少了FOXG1的基因组结合，并提高了ONC201的反应。 方法：在具体目标1中，我们将确定：(I)ClpP线粒体靶向与DRD2的影响 在H3K27M-DMG细胞对ONC201的敏感性中，(Ii)糖酵解与OXPHOS的拮抗作用。以特定的目标 2，我们将确定FOXG1在H3K27M-DMG生物能量学中的作用。在具体目标3中，我们将确定 EGFR抑制对ONC201诱导的H3K27M-DMG线粒体应激及基线的影响 EGFR/FOXG1肿瘤染色预测ONC201疗效我们希望定义EGFR的机制 和FOXG1影响H3K27M-DMG肿瘤的线粒体生物能量学和ONC201敏感性。 意义：这一贡献预计将是重大的，因为它将使临床医生能够优先选择 H3K27M-DMG患者应使用ONC201治疗，并提供合理组合的平台 提高ONC201抗药性的治疗。我们的翻译团队不久将开设一家多站点的国际 平台试验，可以立即对H3K27M-DMG患者实施这一建议的结果。