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: 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
• 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

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 In our unpublished clinical data (n=50 H3K27M patients), ONC201 doubles PFS and overall survival (OS) in some clinical sub-groups (e.g. thalamic H3K27M) with multiple sustained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：具有弥漫性中线神经胶质瘤（DMG）的儿童和年轻人 携带H3K27M突变很少生存超过两年，并且没有可靠的疗法 辐射。多巴胺受体DRD2拮抗剂ONC201诱导TNF相关凋亡的转录 诱导配体（小径），导致多种肿瘤细胞类型的凋亡。 ONC201还结合了 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 活性氧化磷酸化（OXPHOS）。 ONC201在H3K27M-DMG中正在早期使用，但 机制和功效仍然未知。在我们的初步数据中，ONC201在Murine H3 K27M-中有效 突变神经胶质瘤。在我们未发表的临床数据中 一些临床亚组（例如丘脑H3K27M）中的生存（OS），具有多个持续反应。尽管 在H3K27M-DMG中，这种令人印象深刻的功效，我们不知道ONC201如何在H3K27M-DMG肿瘤细胞中起作用或 如何改善抗性肿瘤的反应。 在分析肿瘤测序时，ONC201抗性与EGFR的高表达相关 大脑发育转录因子FOXG1。 FOXG1表达也是最强的负面预测指标 人神经胶质瘤细胞系中的敏感性。为了优先考虑哪些患者 ONC201并产生理由组合疗法，阐明机制有至关重要的需求 H3K27M细胞中的ONC201敏感性。我们的中心假设是ONC201在H3K27M-DMG中有效 通过靶向CLPP的活性OXPHOS的肿瘤，EGFR信号传导介导ONC201电阻 通过通过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的反应有所改善，并且（iii）EGFR 敲低可减少FOXG1基因组结合并改善ONC201的反应。 方法：在特定目标1中，我们将确定：（i）CLPP线粒体靶向与DRD2的影响 拮抗作用和（ii）糖酵解与Oxphos，在H3K27M-DMG细胞对ONC201的敏感性中。在特定目标中 2，我们将确定FOXG1在H3K27M-DMG生物能学中的作用。在特定目标3中，我们将确定 EGFR抑制影响H3K27M-DMG和基线中ONC201诱导的线粒体应力的能力 EGFR/FOXG1肿瘤染色以预测ONC201反应。我们期望定义EGFR的机制 FOXG1影响线粒体生物能学和H3K27M-DMG肿瘤中的ONC201敏感性。 意义：预计此贡献将是重要的，因为它将允许临床医生优先考虑哪个 H3K27M-DMG患者应接受ONC201的治疗，并为理由组合提供平台 改善ONC201阻力的治疗方法。我们的翻译团队将很快开设一个多站点国际 可以立即针对H3K27M-DMG患者实施该提案结果的平台试验。