PET Imaging of Glutamine Metabolism and Glutamate Transport to Guide Metabolically Targeted Therapy in Triple-Negative Breast Cancer
谷氨酰胺代谢和谷氨酸转运的 PET 成像指导三阴性乳腺癌的代谢靶向治疗
基本信息
- 批准号:10624784
- 负责人:
- 金额:$ 51.71万
- 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:2022-05-19 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:Amino AcidsAnabolismAnimal ModelBiological MarkersBreastBreast Cancer CellBreast Cancer ModelCatabolismCell membraneCellsCisplatinCitric Acid CycleClinicClinical MarkersClinical TrialsConsumptionDataDependenceEnzymesExposure toExtracellular FluidFDA approvedGlutamate TransporterGlutamatesGlutamic AcidGlutaminaseGlutamineGlutathioneGrowthHomeostasisHumanImaging DeviceImmunotherapyInterventionKineticsMalignant NeoplasmsMeasuresMediatingMetabolicMetabolic PathwayMetabolismMethodologyMethodsMitochondriaOxidation-ReductionOxidative StressOxidative Stress InductionPaclitaxelPathway interactionsPatient SelectionPatient imagingPatient-derived xenograft models of breast cancerPatientsPatternPharmaceutical PreparationsPharmacodynamicsPlayPositron-Emission TomographyPre-Clinical ModelProductionReactive Oxygen SpeciesReportingResistanceRoleTestingTherapeuticToxic effectTracerTranslatingWorkXenograft Modelalpha ketoglutarateanaloganticancer researchantiporterbiomarker performancebiomarker validationcancer cellcancer clinical trialcell growthchemotherapygenetic signatureimaging agentimaging biomarkerimaging modalityinhibitormalignant breast neoplasmpatient derived xenograft modelpersonalized medicinepharmacodynamic biomarkerpre-clinicalpredicting responsepredictive markerpreservationquantitative imagingrapid growthrefractory cancerresponsetargeted treatmenttherapy designtreatment responsetreatment strategytriple-negative invasive breast carcinomatumortumor growth
项目摘要
Glutaminolysis, the cellular catabolism of glutamine, is an important metabolic pathway
for aggressive and treatment-resistant cancers, including many triple-negative breast
cancers (TNBCs). It is well accepted that glutamate produced from glutamine by
mitochondrial glutaminase (GLS) fuels the TAC cycle, which provides energy and
precursors for biosynthesis. Emerging data have revealed a less recognized but important
contribution of glutaminolysis in mediating oxidative stress introduced internally by active
growth of aggressive cancer cells and externally by treatments including chemotherapy
and immunotherapy. Targeting inhibitors of GLS to block glutaminolysis is a therapeutic
strategy that has been tested in clinical trials of breast and other cancers with acceptable
toxicity, but limited efficacy, owing in good part to a lack of clinical markers to guide patient
selection and assess target impact. Preliminary data from our lab have shown that dual
targeting of GLS and the plasma membrane glutamate transporter, xCT (SLC7A11),
resulted in dramatic sensitization of resistant TNBC to chemotherapy. We propose three
aims based upon an overall theme to develop a kinetic framework for non-metabolized
amino acid analog PET tracers to measure cellular pool sizes as an indicator of
catabolism and cellular transport. Specifically, we will (1) validate quantitative markers for
cellular glutamine pool size from dynamic [18F]fluciclovine PET; (2) develop and validate
markers for cytosolic glutamate pool size and transport using 4-(3-[18F]fluoropropyl)-L-
glutamic acid ([18F]FSPG) PET, and (3) determine the utility of combined [18F]fluciclovine
and [18F]FSPG PET for predicting and measuring response to dual-targeted treatment
designed to sensitize TNBC to chemotherapy. As part of this work, we will address
mechanistic questions regarding cytosolic glutamate transport from mitochondrial pools
and to/from extracellular fluid to guide the interpretation of PET tracer kinetics. We will
also test approaches to target TNBC metabolic vulnerabilities, specifically the
dependence glutamine metabolism and glutamate transport, guided by the PET methods
we develop and validate in our pre-clinical TNBC models. The proposed work will lead
to a deeper understanding of the mutual engagement between glutaminolysis and redox
homeostasis of cancer cells and will yield quantitative imaging methodologies ready to
translate to the clinic.
谷氨酰胺解是谷氨酰胺的细胞分解代谢,是一种重要的代谢途径
项目成果
期刊论文数量(0)
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会议论文数量(0)
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DAVID A. MANKOFF其他文献
DAVID A. MANKOFF的其他文献
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{{ truncateString('DAVID A. MANKOFF', 18)}}的其他基金
PET Imaging of Glutamine Metabolism and Glutamate Transport to Guide Metabolically Targeted Therapy in Triple-Negative Breast Cancer
谷氨酰胺代谢和谷氨酸转运的 PET 成像指导三阴性乳腺癌的代谢靶向治疗
- 批准号:
10342413 - 财政年份:2022
- 资助金额:
$ 51.71万 - 项目类别:
Molecular Imaging Markers for Glutaminolysis in Breast Cancer
乳腺癌谷氨酰胺分解的分子成像标志物
- 批准号:
9215316 - 财政年份:2016
- 资助金额:
$ 51.71万 - 项目类别:
Molecular Imaging Markers for Glutaminolysis in Breast Cancer
乳腺癌谷氨酰胺分解的分子成像标志物
- 批准号:
10056201 - 财政年份:2016
- 资助金额:
$ 51.71万 - 项目类别:
PET to Measure Breast Cancer Bone Metastasis Response
PET 测量乳腺癌骨转移反应
- 批准号:
7318954 - 财政年份:2007
- 资助金额:
$ 51.71万 - 项目类别:
PET to Measure Breast Cancer Bone Metastasis Response
PET 测量乳腺癌骨转移反应
- 批准号:
7450823 - 财政年份:2007
- 资助金额:
$ 51.71万 - 项目类别:
PET to Measure Breast Cancer Bone Metastasis Response
PET 测量乳腺癌骨转移反应
- 批准号:
7640842 - 财政年份:2007
- 资助金额:
$ 51.71万 - 项目类别:
PET to Measure Breast Cancer Bone Metastasis Response
PET 测量乳腺癌骨转移反应
- 批准号:
7885656 - 财政年份:2007
- 资助金额:
$ 51.71万 - 项目类别:
Estrogen Receptor Positive Breast Cancer and Therapy
雌激素受体阳性乳腺癌和治疗
- 批准号:
6984632 - 财政年份:2004
- 资助金额:
$ 51.71万 - 项目类别:
IMAGING FOR EVALUATION OF CLINICAL VACCINE EFFICACY
用于评估临床疫苗功效的成像
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6563974 - 财政年份:2002
- 资助金额:
$ 51.71万 - 项目类别:
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