In Vivo Imaging of Mitochondria Structure and Function in Therapy Resistant Lung Tumors
难治性肺肿瘤线粒体结构和功能的体内成像
基本信息
- 批准号:10747207
- 负责人:
- 金额:$ 4.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAmericanAreaBiguanidesBioenergeticsBiological MarkersBiopsyCancer PatientCell LineCell RespirationClassificationClinicalComplexDataDependenceDiagnosisDiagnosticDiseaseDisease ResistanceDissectionElectron TransportEpidermal Growth Factor ReceptorExhibitsFunctional ImagingGene Expression ProfilingGenetically Engineered MouseGoalsHealthHumanImmuno-ChemotherapyImmunotherapyKRAS2 geneKnowledgeLung AdenocarcinomaLung NeoplasmsMaintenanceMalignant neoplasm of lungMeasuresMembrane PotentialsMetabolicMetabolic PathwayMetabolismMitochondriaMutationNon-Small-Cell Lung CarcinomaOncogenicOxidative PhosphorylationPatientsPhenotypePhosphorylation InhibitionPhysiologicalPositron-Emission TomographyRationalizationResearchResistanceResistance developmentSTK11 geneSiteSpirometryStructureSurvival RateTestingTherapeuticTimeTracerTyrosine Kinase InhibitorWorkadvanced diseasecancer therapycheckpoint therapydiagnostic strategydriver mutationfluorodeoxyglucoseimage guidedimaging probeimprovedin vivoin vivo imaginginhibitormetabolic profilemitochondrial membranemitochondrial metabolismmutantnano-stringneoplastic cellnovelnovel diagnosticsnovel strategiesnovel therapeutic interventionnovel therapeuticspatient derived xenograft modelstemsuperresolution microscopytargeted treatmenttherapy developmenttherapy resistanttreatment responsetumortumor initiationtumor metabolismuptake
项目摘要
Abstract
The overarching goal of this study is to identify effective metabolic based diagnostic and therapeutic strategies
to improve the overall survival of patients with Non-small cell lung cancer (NSCLC). We propose to investigate
the positron emission tomography (PET) tracer, 18F-BnTP as a novel metabolic diagnostic and to develop
metabolic based therapeutic strategies targeting oxidative mitochondrial metabolism in therapy resistant
KRAS/LKB1 and EGFR mutant lung tumors. NSCLC will claim the lives of ~130,000 in the US in 2021. Lung
tumors frequently possess a high mutational burden, often rendering single agent therapies targeting
oncogenic driver mutations unsuccessful. Furthermore, metabolically active subsets of lung adenocarcinomas
(LUADs) bearing mutations in KRAS and LKB1 or EGFR are frequently resistant to immunotherapy
approaches. However, regardless of the initials benefits from checkpoint inhibitors or targeted therapies, the
majority of patients will eventually develop resistance to therapy. We rationalize a different approach to
overcoming therapy resistance in NSCLC – namely the classification of tumors by their metabolic signature.
Here, tumors are grouped and targeted by their metabolic dependencies rather than solely by their genetic
alterations. NSCLC is a metabolically heterogeneous disease and tumors utilize both glycolytic and oxidative
mitochondrial metabolism to grow. The mitochondria are the site of cellular bioenergetics and oxidative
phosphorylation (OXPHOS) and are essential for lung tumor initiation and maintenance. Due to a lack of in
vivo imaging probes there is a gap in our knowledge at a physiological and mechanistic level of how
mitochondrial bioenergetics are regulated in NSCLC. To address this gap, we functionally imaged
mitochondrial activity in lung tumors utilizing the PET imaging tracer 18F-BnTP and demonstrate that it
functions an in vivo biomarker of mitochondrial membrane potential (ΔΨ) and oxidative phosphorylation
(OXPHOS) in lung tumors3. Importantly, by using 18F-BnTP PET imaging we are able to distinguish between
OXPHOS dependent and independent lung tumors. Therapeutically, we have demonstrated that 18F-BnTP
positive, OXPHOS-dependent LUADs are sensitive to mitochondrial complex I inhibitors. We hypothesize that
18F-BnTP PET imaging can be utilized to functionally profile mitochondrial bioenergetics and adaptive oxidative
metabolism in therapy-resistant lung tumors to guide treatment with OXPHOS inhibitors. In aim 1 we will
perform an in vivo dissection of mitochondrial bioenergetics in therapy-resistant LUADs. In aim 2 we will
perform a structural and functional in vivo analysis of adaptive oxidative metabolism in therapy-resistant
KRAS/LKB1 and EGFR mutant LUADs. In Aim 3 we will longitudinally profile oxidative metabolism in LUAD
patients with advanced disease. The proposed work has relevance to human health in which we propose that
18F-BnTP PET imaging guided targeting and oxidative metabolism represents a new therapeutic strategy to
overcome therapy resistance in patients with KRAS/LKB1 and EGFR mutant tumors.
摘要
项目成果
期刊论文数量(0)
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David B Shackelford其他文献
David B Shackelford的其他文献
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{{ truncateString('David B Shackelford', 18)}}的其他基金
In vivo imaging of mitochondria structure and function in therapy resistant lung tumors
治疗耐药性肺肿瘤线粒体结构和功能的体内成像
- 批准号:
10866660 - 财政年份:2022
- 资助金额:
$ 4.07万 - 项目类别:
In vivo imaging of mitochondria structure and function in therapy resistant lung tumors
治疗耐药性肺肿瘤线粒体结构和功能的体内成像
- 批准号:
10522994 - 财政年份:2022
- 资助金额:
$ 4.07万 - 项目类别:
In vivo imaging of mitochondria structure and function in therapy resistant lung tumors
治疗耐药性肺肿瘤线粒体结构和功能的体内成像
- 批准号:
10649562 - 财政年份:2022
- 资助金额:
$ 4.07万 - 项目类别:
(PQ5) Imaging mitochondrial heterogeneity in LKB1 mutant lung cancer
(PQ5) LKB1 突变肺癌线粒体异质性成像
- 批准号:
9750637 - 财政年份:2016
- 资助金额:
$ 4.07万 - 项目类别:
Imaging mitochondrial heterogeneity in LKB1 mutant lung cancer
LKB1 突变肺癌线粒体异质性成像
- 批准号:
9392856 - 财政年份:2016
- 资助金额:
$ 4.07万 - 项目类别:
Imaging mitochondrial heterogeneity in LKB1 mutant lung cancer
LKB1 突变肺癌线粒体异质性成像
- 批准号:
9403002 - 财政年份:2016
- 资助金额:
$ 4.07万 - 项目类别:
(PQ5) Imaging mitochondrial heterogeneity in LKB1 mutant lung cancer
(PQ5) LKB1 突变肺癌线粒体异质性成像
- 批准号:
10063382 - 财政年份:2016
- 资助金额:
$ 4.07万 - 项目类别:
Imaging mitochondrial heterogeneity in LKB1 mutant lung cancer
LKB1 突变肺癌线粒体异质性成像
- 批准号:
10585832 - 财政年份:2016
- 资助金额:
$ 4.07万 - 项目类别:
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