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.

项目总结