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
基本信息
- 批准号:10536455
- 负责人:
- 金额:$ 4.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdultAffectAftercareAminolevulinic AcidApoptosisAstrocytesBehaviorBioinformaticsBiological AssayBloodBlood - brain barrier anatomyBlood VesselsBrainBrain NeoplasmsBrain StemBromodeoxyuridineCause of DeathCell Culture TechniquesCell Cycle ArrestCell DeathCell ProliferationCell SurvivalCellsCentral Nervous System NeoplasmsChildChildhoodChildhood Brain NeoplasmChildhood Brain Stem NeoplasmClinical TrialsCombined Modality TherapyCyclic AMP-Dependent Protein KinasesDataData SetDiagnosisDiffuse intrinsic pontine gliomaDisease OutcomeDrug Delivery SystemsExtracellular Signal Regulated KinasesFlow CytometryFutureGene Expression ProfileGeneticGenetically Engineered MouseGliomaImmune EvasionImmune TargetingImmune responseIn VitroKnock-outLightMAP Kinase GeneMalignant - descriptorMalignant Childhood NeoplasmMalignant NeoplasmsMalignant neoplasm of brainMitogen-Activated Protein Kinase InhibitorMitogen-Activated Protein Kinase KinasesMitogen-Activated Protein KinasesModalityModelingMolecularMorbidity - disease rateMusMutationNeuraxisOncogenicPUVA PhotochemotherapyPathway interactionsPatientsPatternPhenotypePhotosensitizing AgentsPrognosisPropidium DiiodideProtein KinaseProteomicsRadiation therapyReactive Oxygen SpeciesReceptor Protein-Tyrosine KinasesRoleSamplingSignal PathwaySignal TransductionSliceSpecimenStainsStromal CellsSubgroupTestingTherapeuticTracerTranslationsTreatment EfficacyTreatment-related toxicityTumor BurdenUnited StatesWestern Blottingaggressive therapyantitumor effectcancer cellcell injurycell killingcell motilitydiagnostic tooldiffuse midline gliomaeffective therapyexperimental studyextracellulargenetic signatureimmunocytochemistryimmunoregulationimprovedin vivoinnovationinterestmortalitymouse modelneoplastic cellnerve stem cellpleiotropismpreclinical trialprotoporphyrin IXsingle-cell RNA sequencingstandard of caretranscriptomicstreatment responsetumortumor microenvironmenttumorigenesis
项目摘要
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
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Gabrielle Alexia Price其他文献
Gabrielle Alexia Price的其他文献
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{{ truncateString('Gabrielle Alexia Price', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 4.66万 - 项目类别:
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