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: 10733440
• 负责人: Gabrielle Alexia Price
• 金额: $ 4.61万
• 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/10733440
• 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 Death Induction; Cell Proliferation; Cell Survival; Cells; Central Nervous System; Central Nervous System Neoplasms; Child; Childhood; Childhood Brain Neoplasm; Childhood Brain Stem Neoplasm; Clinical Trials; Combined Modality Therapy; 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; Inhibition of Cell Proliferation; Invaded; Knock-out; Light; MAP Kinase Gene; MAPK3 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; 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; Treatment Efficacy; Treatment-related toxicity; Tumor Burden; United States; Western Blotting; aggressive therapy; antitumor effect; blood-brain barrier disruption; cancer cell; cell injury; cell killing; cell motility; diagnostic tool; diffuse midline glioma; effective therapy; experimental study; extracellular; extracellular signal-regulated kinase 3; 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; synergism; transcriptomics; translational therapeutics; 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.

项目概要 弥漫性中线胶质瘤（DMG），包括弥漫性内在桥脑胶质瘤（DIPG），是有害的恶性 小儿脑干肿瘤。 DMG 是儿童脑肿瘤死亡的主要原因 儿童中第二常见的恶性脑癌。 DMG 的预后较差，低于 1% 即使使用最积极的治疗，诊断后一年内仍能存活。约400名儿童 将于 2022 年在美国被诊断出患有 DIPG，所有患者的中位生存期将在 8 岁之间 和11个月。由于缺乏有效的治疗方法，DMG 疾病的结果在过去十年中已趋于稳定。 治疗和有限的诊断工具。许多失败的 DMG 临床试验和治疗策略可以 归因于两个关键问题：1）选择性穿透血脑屏障（BBB）限制药物输送 对中枢神经系统的影响，以及 2）尽管 DMG 和成人高危人群之间存在明显的遗传改变 级神经胶质瘤 (aHGG)，考虑用于 DMG 临床试验的药物是通过外推得出的 aHGG 数据，没有治疗翻译的依据。研究表明细胞外信号调节 蛋白激酶 (ERK) 是丝裂原激活蛋白激酶 (MEK) 的下游受体酪氨酸激酶， DMG 中上调，引发了关于靶向 MAPK/ERK 通路是否可以具有抗肿瘤作用的疑问 DMG 中的效果。靶向 MEK 与氨基乙酰丙酸光动力疗法 (5-ALA-PDT) 相结合 之所以引起人们的兴趣，是因为已发现抑制 MEK 可以显着增强原卟啉 IX (PpIX) 以肿瘤特异性方式在体外和体内积累。该提案采用创新的多式联运 解决 DMG 临床试验成功的障碍并利用分子生物学的治疗方法 DMG 细胞的组成以降低发病率和死亡率。通过以 MEK 为目标并采用 5-ALA-PDT，我们 预计 MEK 抑制将与 5-ALA-PDT 功效协同作用，通过引发直接肿瘤细胞杀伤、血管 关闭和免疫反应，最终提高患者的总体生存率。如果成功的话，这种治疗可以 适用于其他不能手术的中枢神经系统肿瘤。