MEK PATHWAY INHIBITION COMBINED WITH 5-AMINOLEVULINIC ACID-PHOTODYNAMIC THERAPY FOR THE TREATMENT OF DIFFUSE MIDLINE GLIOMA

MEK 通路抑制联合 5-氨基酮戊酸光动力疗法治疗弥漫性中线胶质瘤

• 批准号: 10536455
• 负责人: Gabrielle Alexia Price
• 金额: $ 4.66万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-26 至 2026-09-25
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536455
• 关键词: Address; Adult; Affect; Aftercare; Aminolevulinic Acid; Apoptosis; Astrocytes; Behavior; Bioinformatics; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Neoplasms; Brain Stem; Bromodeoxyuridine; Cause of Death; Cell Culture Techniques; Cell Cycle Arrest; Cell Death; Cell Proliferation; Cell Survival; Cells; Central Nervous System Neoplasms; Child; Childhood; Childhood Brain Neoplasm; Childhood Brain Stem Neoplasm; Clinical Trials; Combined Modality Therapy; Cyclic AMP-Dependent Protein Kinases; Data; Data Set; Diagnosis; Diffuse intrinsic pontine glioma; Disease Outcome; Drug Delivery Systems; Extracellular Signal Regulated Kinases; Flow Cytometry; Future; Gene Expression Profile; Genetic; Genetically Engineered Mouse; Glioma; Immune Evasion; Immune Targeting; Immune response; In Vitro; Knock-out; Light; MAP Kinase Gene; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of brain; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Neuraxis; Oncogenic; PUVA Photochemotherapy; Pathway interactions; Patients; Pattern; Phenotype; Photosensitizing Agents; Prognosis; Propidium Diiodide; Protein Kinase; Proteomics; Radiation therapy; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Role; Sampling; Signal Pathway; Signal Transduction; Slice; Specimen; Stains; Stromal Cells; Subgroup; Testing; Therapeutic; Tracer; Translations; Treatment Efficacy; Treatment-related toxicity; Tumor Burden; United States; Western Blotting; aggressive therapy; antitumor effect; cancer cell; cell injury; cell killing; cell motility; diagnostic tool; diffuse midline glioma; effective therapy; experimental study; extracellular; genetic signature; immunocytochemistry; immunoregulation; improved; in vivo; innovation; interest; mortality; mouse model; neoplastic cell; nerve stem cell; pleiotropism; preclinical trial; protoporphyrin IX; single-cell RNA sequencing; standard of care; transcriptomics; treatment response; tumor; tumor microenvironment; tumorigenesis

PROJECT SUMMARY Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), are deleterious malignant pediatric tumors of the brainstem. DMG is the leading cause of death among pediatric brain tumors and the second most common malignant brain cancer afflicting children. DMG has a dismal prognosis of less than 1% survival within a year of diagnosis, even when using the most aggressive treatments. Approximately 400 children will be diagnosed with DIPG in the United States in 2022, all of whom will have a median survival of between 8 and 11 months. DMG disease outcomes have plateaued over the past decade due to the lack of effective treatments and limited diagnostic tools. Many failed clinical trials and therapeutic strategies in DMG can be attributed to two critical concerns: 1) the selectively penetrable blood brain barrier (BBB) restricts drug delivery to central nervous system, and 2) despite there being distinct genetic alterations between DMG and adult high- grade gliomas (aHGG), the agents considered for DMG clinical trials have been derived by extrapolation from aHGG data, without grounds for the therapeutic translation. Studies have revealed extracellular signal-regulated protein kinases (ERK), a downstream receptor tyrosine kinase of mitogen-activated protein kinase (MEK), is upregulated in DMG, raising questions about whether targeting the MAPK/ERK pathway can have anti-tumor effects in DMG. Targeting MEK in combination with aminolevulinic acid-photodynamic therapy (5-ALA-PDT) is of interest because inhibition of MEK has been found to significantly enhance protoporphyrin IX (PpIX) accumulation in vitro and in vivo in a tumor-specific manner. This proposal uses an innovative multimodal treatment approach that addresses the barriers to successful DMG clinical trials and exploits the molecular composition of DMG cells to reduce morbidity and mortality. By targeting MEK and employing 5-ALA-PDT, we anticipate MEK inhibition will synergize with 5-ALA-PDT efficacy by eliciting direct tumor cell killing, vascular shutdown and immune response, ultimately increasing overall patient survival. If successful, this treatment can be applied to other inoperable CNS tumors.

项目摘要 弥漫性中线神经胶质瘤（DMG），包括弥漫性固有pontine gliomas（DIPG），是有害的恶性肿瘤 脑干的小儿肿瘤。 DMG是小儿脑肿瘤中死亡的主要原因和 第二个最常见的恶性脑癌困扰儿童。 DMG的预后低于1％ 即使使用最具侵略性的治疗，也可以在诊断的一年内生存。大约400名儿童 将于2022年在美国被诊断出患有DIPG，所有这些人的中位生存期为8 和11个月。 DMG疾病结果在过去十年中由于缺乏有效 治疗和有限的诊断工具。许多DMG中的许多临床试验和治疗策略失败可能是 归因于两个关键问题：1）选择性渗透性血脑屏障（BBB）限制了药物输送 到中枢神经系统，2）尽管DMG和成人高 - gliomas（AHGG），考虑到DMG临床试验的药物是通过推断来得出的 AHGG数据，没有治疗翻译的理由。研究表明细胞外信号调节 蛋白激酶（ERK）是一种下游受体酪氨酸激酶的有丝分裂原激活蛋白激酶（MEK）的蛋白质激酶，是 在DMG中上调，提出了有关靶向MAPK/ERK途径是否具有抗肿瘤的问题 DMG的影响。靶向MEK与氨基乙烯酸 - 运动动力疗法（5-ALA-PDT）的靶向为 有趣的是，发现MEK的抑制显着增强了原源性IX（PPIX） 以肿瘤特异性方式在体外和体内积累。该建议使用创新的多模式 处理成功DMG临床试验的障碍并利用分子的治疗方法 DMG细胞的组成以降低发病率和死亡率。通过针对MEK并使用5-Ala-PDT，我们 预期MEK抑制作用将通过引起直接肿瘤细胞，血管来与5-ALA-PDT疗效协同 关闭和免疫反应，最终增加了总体患者生存率。如果成功，这种治疗可以 应用于其他无法使用的中枢神经系统肿瘤。