Defining the role of mitochondrial injury in MEK inhibitor cardiotoxicity
Defining the role of mitochondrial injury in MEK inhibitor cardiotoxicity
批准号:
10753009
负责人:
Brian C Jensen
金额:
$53.36万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-08-11 至 2027-07-31
关键词:
Adverse effectsAllosteric RegulationBRAF geneBioenergeticsBiologyBreast Cancer CellCardiacCardiac MyocytesCardiomyopathiesCardiotoxicityCessation of lifeClinical TrialsCombined Modality TherapyCommon NeoplasmComplexCoupledDataElectron TransportEtiologyExtracellular Signal Regulated KinasesFDA approvedFunctional disorderFutureGeneticHeartHeart InjuriesHeart MitochondriaHeart failureHumanImmuneImmune checkpoint inhibitorImmune responseImpairmentIn VitroInflammationInflammatoryInjuryInnate Immune ResponseLifeMAP2K1 geneMAPK3 geneMEK inhibitionMEKsMalignant NeoplasmsMediatingMitochondriaMolecularMusMuscle FibersMyocardialOxidative PhosphorylationOxidative StressOxidative Stress InductionPathway interactionsPatientsPatternPattern recognition receptorPermeabilityPhasePhenotypePhosphorylationPhysiologyProcessPublishingRas/RafReactionRegulationResearch PersonnelRiskRoleSTAT3 geneTestingTherapeuticToxic effectTranscriptWorkanti-cancercancer cellcancer therapycardiovascular effectsclinically relevantcombination cancer therapycomplex IVcytokinediagnostic platformexperimental studygenetic manipulationimmune activationin vivoinhibitorinjuredinnate immune pathwaysmelanomamouse modelnovelpharmacologicpre-clinicalprogrammed cell death ligand 1respiratorytargeted cancer therapytargeted treatmenttranscriptome sequencingtranscriptomicstriple-negative invasive breast carcinomatumortumorigenesis
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
Persistent hyperactivation of the Ras-Raf-MEK-ERK pathway contributes to oncogenesis in over 30% of human
cancers. Trametinib (Trm) is a highly selective inhibitor of MEK1, the sole upstream activator of multifunctional
pro-survival kinases ERK1/2. Trm commonly is used in combination with dabrafenib to prolong life in patients
with melanoma; its efficacy in other common tumor types including triple negative breast cancer (TNBC) is being
widely explored. Trm generally is well tolerated, though it can cause cardiomyopathy that may lead to heart
failure (HF) in up to 11% of cases. The mechanisms underlying Trm-associated cardiotoxicity are unclear. Our
preliminary data show that 14-day Trm treatment abrogated mouse myocardial ERK1/2 activation and induced
reversible cardiac contractile dysfunction characterized by reduced mitochondrial abundance and compromised
oxidative phosphorylation in vivo. RNAseq analysis of Trm-treated mouse hearts revealed broad decreases in
mitochondrial transcripts and increases in immune response pathways that are molecularly distinct from other
HF etiologies. In vitro exposure of primary cardiomyocytes to Trm caused mitochondrial injury and activated
canonical inflammatory pathways. These surprising effects were not predicted by our current understanding of
MEK-ERK cardiomyocyte biology or by our understanding of the anticancer mechanisms of MEK inhibitors
(MEKi’s). Here we will use 3 specific aims to test the central hypothesis that MEK-ERK inhibition impairs
OXPHOS to induce mitochondrial injury resulting in innate immune activation, and that these effects collectively
contribute to both the cardiotoxicity and anticancer efficacy of Trm. In the mechanistic Aim 1 we will find if Trm
induces mitochondrial injury by compromising oxidative phosphorylation and inducing oxidative stress. Aim 2
will determine whether genetic or pharmacological loss of MEK function is sufficient to induce cardiomyocyte
mitochondrial injury using novel mouse models of cardiomyocyte MEK1 deficiency and other FDA-approved
pharmacological MEKi’s. Aim 3 will test whether Trm-induced mitochondrial toxicity activates innate immune
responses in cardiomyocytes and cancer cells using a validated mouse model of TNBC and a clinically relevant
combination targeted therapy. These studies will establish whether activation of pattern recognition receptors
by mitochondrial damage associated molecular patterns contributes to Trm cardiotoxicity or anticancer efficacy,
and will define whether the addition of Trm to an immune checkpoint inhibitor enhances cardiotoxic risk. The
proposed experiments have the potential to impact the fields of myocardial biology and cancer therapeutics in
related but distinct ways: (1) Expand our understanding of MEK-ERK regulation of cardiomyocyte mitochondrial
function; (2) Identify the molecular processes that contribute to Trm cardiotoxicity; (3) Determine whether
mitochondrial toxicity and innate immune activation contribute to the anticancer efficacy of Trm and other MEKi’s.
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会议论文
Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation
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批准号:10587727
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项目类别:
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资助金额:$58.51万
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财政年份:2017
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负责人:Brian C Jensen
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依托单位:
Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation
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批准号:10318139
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项目类别:
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资助金额:$38.88万
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财政年份:2017
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Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation
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批准号:10067377
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项目类别:
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资助金额:$38.88万
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财政年份:2017
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负责人:Brian C Jensen
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依托单位:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
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批准号:8131703
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项目类别:
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资助金额:$13.24万
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财政年份:2009
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负责人:Brian C Jensen
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依托单位:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
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批准号:8496578
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项目类别:
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资助金额:$13.24万
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财政年份:2009
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负责人:Brian C Jensen
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依托单位:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
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批准号:7707444
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项目类别:
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资助金额:$13.3万
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财政年份:2009
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负责人:Brian C Jensen
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依托单位:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
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批准号:8294717
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项目类别:
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资助金额:$13.24万
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财政年份:2009
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负责人:Brian C Jensen
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依托单位:
Alpha-1-Adrenergic Receptor Subtypes in the Cells of the Human Heart
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批准号:7919951
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项目类别:
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资助金额:$13.24万
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财政年份:2009
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负责人:Brian C Jensen
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依托单位:
海外基金