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Project 3: Identifying and targeting mediators of CNS metastasis from lung cancer

Project 3: Identifying and targeting mediators of CNS metastasis from lung cancer
项目3:识别和靶向肺癌中枢神经系统转移的介质
批准号:
10203856
负责人:
Don X Nguyen
金额:
$39.01万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
未结题
起止时间:
2015-08-26 至 2025-07-31
关键词:
BiologicalBiopsyBlood - brain barrier anatomyBlood VesselsBrainBrain NeoplasmsCDK4 geneCancer BiologyCancer PatientCellsCentral Nervous System DiseasesCentral Nervous System NeoplasmsCerebrospinal FluidClinicalClinical PathwaysClinical TrialsComplementCraniotomyDNA Sequence AlterationDiagnosisDiagnosticDiseaseDrug resistanceEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEpigenetic ProcessGene ExpressionGene MutationGeneticGenomic approachGrowthHumanIn SituIncidenceKDR geneLigandsLiquid substanceMalignant neoplasm of lungMalignant neoplasm of thoraxMediator of activation proteinMetastatic Neoplasm to the Central Nervous SystemMetastatic malignant neoplasm to brainMethodsModelingMolecularMolecular AnalysisMonoclonal AntibodiesMutationMyelogenousNeoplasm MetastasisNeuraxisNon-Small-Cell Lung CarcinomaOutcomePathway interactionsPatientsPatternPharmaceutical PreparationsPlasmaPre-Clinical ModelProgression-Free SurvivalsProtocols documentationQuality of lifeRefractoryRelapseResistanceRiskSignal TransductionSourceSpecimenSpinal NeoplasmsSpinal PunctureStromal NeoplasmTestingTherapeuticTimeTumor TissueTyrosine Kinase InhibitorVascular Endothelial Growth FactorsVascular remodelingactionable mutationbeta cateninbevacizumabcerebral microvasculatureclinically actionablecohortdriver mutationeffective therapyexome sequencinggenetic evolutionimprovedin vivoinsightinterdisciplinary approachmolecular markermutantneoplastic cellnotch proteinnovelpatient derived xenograft modelpersonalized medicinephase II trialpreventprospectivereceptor expressionresponseresponse biomarkertargeted agenttranscriptomicstumortumor DNAtumor microenvironmenttumor progression

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中文摘要
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英文摘要
PROJECT SUMMARY Lung cancers are the major source of metastasis in the central nervous system (CNS). There is an important gap in our understanding of how brain metastases respond to therapies and what mechanisms sustain metastatic tumors in the CNS. Historically, the blood brain barrier has been viewed as an impediment to systemic drugs, and novel brain penetrant agents such as the mutant EGFR inhibitor osimertinib have been developed. However, despite improved clinical responses with these agents, brain metastases still progress, and it is unknown how perturbations in the brain tumor microenvironment (TME) can be leveraged for more effective treatments in patients with CNS disease. We have developed novel methods to molecularly characterize human cerebral spinal fluid (CSF) as well as distinguish tumor from stromal gene alterations of brain metastasis in vivo. Our approaches uncover genetic mutations as well as brain TME induced alterations that converge onto cooperating pathways, such as those regulated by VEGF, NOTCH, β-catenin and PI3K. We hypothesize that these molecular alterations: 1) cooperatively drive NSCLC brain metastasis and drug resistance in the brain, 2) are clinically actionable, and 3) are more accurately detected in human CSF or brain biopsies, due to divergent genetic evolution and TME induced adaptation of brain metastasis. Our hypothesis will be studied in 3 independent yet complimentary aims. In Aim1, we propose to collect human CSF from craniotomies as well as lumbar punctures of lung cancer patients with brain metastases who will be undergoing a bronchoscopic biopsy. By comparing the mutational landscape of matched CSF, plasma and tumor tissue, we will molecularly characterize humans with asymptomatic brain metastasis. Moreover, we will use novel orthotopic patient derived xenograft models (PDXs) to determine if brain metastasis progression and drug response correlates with co-occurring mutations identified in human CSF. In Aim 2, we will test the novel hypothesis that an activated brain microvasculature enhances the survival of drug resistant tumor cells via stromal induced NOTCH signaling in vivo. We will assess if novel bi-specific agents which simultaneously inhibit VEGF and NOTCH can delay brain metastasis progression and/or improve osimertinib response in pre-clinical models. Using human biospecimens, we will correlate the expression of VEGF and NOTCH pathway components with brain metastatic relapse. In Aim 3, we will conduct a clinical trial combining a mutation specific TKI (osimertinib) with a brain vascular targeting agent (bevacizumab) in treatment naïve lung cancer patients with EGFR mutant tumors and CNS disease. Finally, molecular markers (including those studied in Aims 1 and 2) of response or resistance to this combination will be identified by analyzing CSF, plasma and tumor biopsies. This proposal will help uncover the biological basis of brain metastasis relapse. Importantly, our study will generate insight as to how current and prospective therapies can be harnessed to target both tumor specific mutations and the TME, in a manner that improves clinical outcomes for lung cancer patients with CNS disease.
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会议论文
Uncovering the Biology of Resistance to Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Patient-Derived Models.
  • 批准号:
    9920134
  • 项目类别:
  • 资助金额:
    $79.81万
  • 财政年份:
    2019
  • 负责人:
    Don X Nguyen
  • 依托单位:
Uncovering the Biology of Resistance to Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Patient-Derived Models.
  • 批准号:
    10376749
  • 项目类别:
  • 资助金额:
    $74.93万
  • 财政年份:
    2019
  • 负责人:
    Don X Nguyen
  • 依托单位:
Uncovering the Biology of Resistance to Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Patient-Derived Models.
  • 批准号:
    10616672
  • 项目类别:
  • 资助金额:
    $72.9万
  • 财政年份:
    2019
  • 负责人:
    Don X Nguyen
  • 依托单位:
A novel lineage pathway controls metabolic adaptation by metastatic lung cancers
  • 批准号:
    8984877
  • 项目类别:
  • 资助金额:
    $38.03万
  • 财政年份:
    2014
  • 负责人:
    Don X Nguyen
  • 依托单位:
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