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.

项目总结 弥漫性中线胶质瘤(DMG)，包括弥漫性固有桥脑胶质瘤(DIPG)，是恶性的 儿童脑干肿瘤。DMG是导致儿童脑肿瘤死亡的主要原因， 儿童第二常见的恶性脑癌。DMG的预后不到1% 确诊后一年内存活，即使在使用最积极的治疗时也是如此。大约400名儿童 将于2022年在美国被诊断为DIPG，所有人的中位生存期都将在8 还有11个月。由于缺乏有效的治疗方法，DMG疾病的结局在过去十年中一直停滞不前。 治疗和有限的诊断工具。DMG中许多失败的临床试验和治疗策略可能是 归因于两个关键问题：1)选择性可穿透血脑屏障(BBB)限制药物输送 2)尽管DMG和成人高血压病之间存在明显的基因改变- 级别胶质瘤(AHGG)，考虑用于DMG临床试验的药物是通过外推得出的 AHGG数据，没有治疗性翻译的依据。研究揭示了细胞外信号调节 蛋白激酶(ERK)是丝裂原活化蛋白激酶(MEK)的下游受体酪氨酸激酶。 在DMG中上调，引发了靶向MAPK/ERK通路是否具有抗肿瘤作用的问题 DMG中的效果。靶向MEK联合氨基酮戊酸-光动力疗法(5-ALA-PDT)是 有趣的是，已经发现抑制MEK可以显著增强原卟啉IX(PpIX) 在体外和体内以肿瘤特异性的方式蓄积。该提案使用了创新的多式联运 治疗方法，解决了DMG临床试验成功的障碍，并利用分子 DMG细胞的成分可降低发病率和死亡率。通过针对MEK和使用5-ALA-PDT，我们 预期抑制MEK将通过诱导直接的肿瘤细胞杀伤、血管生成而与5-ALA-PDT的疗效协同 关机和免疫反应，最终提高患者的总体存活率。如果成功，这种治疗方法可以 适用于其他不能手术的中枢神经系统肿瘤。