Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
基本信息
- 批准号:9763831
- 负责人:
- 金额:$ 37.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-15 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:70-kDa Ribosomal Protein S6 KinasesA/J MouseAddressAnimalsAutophagocytosisBioenergeticsBrainCancer EtiologyCarboxylic AcidsCell CompartmentationCell DeathCell LineCell ProliferationCell modelCessation of lifeChemicalsChemopreventionChemopreventive AgentClinicalClinical TrialsComplexDataDevelopmentDiseaseDoseDrug TargetingElectron TransportFRAP1 geneFutureGenerationsGoalsGrowthHumanIn VitroIndazolesIndividualLinkLonidamineLungLung NeoplasmsMagnetic Resonance ImagingMalignant NeoplasmsMalignant neoplasm of lungMediatingMetabolicMetastatic Neoplasm to the LungMetastatic malignant neoplasm to brainMitochondriaModificationMolecularMonitorMusNeoplasm MetastasisOxidation-ReductionPathway interactionsPatientsPatternPharmacologyPrevention strategyPreventivePrimary NeoplasmProto-Oncogene Proteins c-aktReactive Oxygen SpeciesResearchSignal TransductionStressSystemTestingTimeToxic effectTumor BurdenUnited Statesaerobic glycolysisanaloganimal imaginganti-cancerbioluminescence imagingbrain tissuecancer cellcarcinogenesisdesigngenetic approachimaging modalityimprovedin vitro Modelin vivoin vivo Modelinhibitor/antagonistinnovationlung metastaticlung tumorigenesismouse modelneoplastic cellnovelnovel strategiesperoxiredoxinpre-clinicalpreneoplastic cellpreventtargeted agenttumortumor metabolismtumor progression
项目摘要
PROJECT SUMMARY
Lung cancer is the leading cause of cancer death in the United States. The development of new and effective
chemopreventive agents for lung cancer is urgently needed. Our long-term goal is to identify and advance new
and efficacious preventive agents targeting human lung cancer. There is growing evidence that distinct tumor-
specific metabolic changes, including reliance on aerobic glycolysis and changes in mitochondrial bioenergetics,
are key drivers of malignancy. We made chemical modifications to lonidamine (LON), an anti-glycolytic
compound with limited anti-tumor efficacy, to create Mito-LON as a more effective and safe mitochondria-
targeted, tumor cell selective agent with a new mechanism, specifically OXPHOS inhibition. Our preliminary data
show that Mito-LON, at low micromolar concentrations, is a potent inhibitor of cancer cell mitochondrial
bioenergetics, and results in pronounced mitigation of lung cancer development, cell proliferation, growth,
progression, and metastasis. We hypothesize that Mito-LON inhibits lung tumor development and metastasis
through induction of autophagic cell death (ACD) by suppressing mitochondrial complexes I and II, depleting
cellular ATP, stimulating ROS formation, and subsequent effects on AKT/mTOR/p70S6K signaling. We will test
our hypothesis in three specific aims. Aim 1 will determine the effects of Mito-LON on mitochondrial bioenergetics
and redox status in cellular systems in vitro. Aim 2 will determine the capacity of Mito-LON to induce ACD, with
a focus on mitophagy, as a mechanism to mitigate lung cancer progression and metastasis. Aim 3 will determine
the capacity of Mito-LON to inhibit lung tumor progression and lung cancer brain metastasis in vivo. We will use
state-of-the-art small animal imaging to monitor the growth of primary tumors (using magnetic resonance
imaging) and brain metastasis (through bioluminescence imaging). Successful completion of these aims will
increase our understanding of the molecular basis of autophagy in the context of lung cancer inhibition and more
broadly establish a new approach for using mitochondria-targeting drugs to effectively and selectively block
cancer cell metabolism, energy generation, and induce ACD. This proposal is timely and significant since future
clinical trials of Mito-LON against lung cancer will require vigorous preclinical characterization of the efficacy and
precise mechanisms of action in targeting cancer metabolism.
项目总结
项目成果
期刊论文数量(0)
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BALARAMAN KALYANARAMAN其他文献
BALARAMAN KALYANARAMAN的其他文献
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{{ truncateString('BALARAMAN KALYANARAMAN', 18)}}的其他基金
Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
- 批准号:
9915863 - 财政年份:2019
- 资助金额:
$ 37.89万 - 项目类别:
Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
- 批准号:
10489835 - 财政年份:2019
- 资助金额:
$ 37.89万 - 项目类别:
Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
- 批准号:
10687020 - 财政年份:2019
- 资助金额:
$ 37.89万 - 项目类别:
Chemoprevention of lung cancer by targeting lonidamine to mitochondria
通过将氯尼达明靶向线粒体来化学预防肺癌
- 批准号:
10476701 - 财政年份:2019
- 资助金额:
$ 37.89万 - 项目类别:
Chemoprevention of Lung Cancer with Mitochondria-Targeted Honokiol
利用线粒体靶向和厚朴酚化学预防肺癌
- 批准号:
10497449 - 财政年份:2017
- 资助金额:
$ 37.89万 - 项目类别:
Chemoprevention of lung cancer with mitochondria-targeted honokiol
线粒体靶向和厚朴酚对肺癌的化学预防
- 批准号:
10092125 - 财政年份:2017
- 资助金额:
$ 37.89万 - 项目类别: