Melanoma: Metabolic Biomarkers of Response to Targeted Therapy
黑色素瘤:靶向治疗反应的代谢生物标志物
基本信息
- 批准号:10115684
- 负责人:
- 金额:$ 47.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AlanineBRAF geneBiochemicalBiochemical PathwayBiochemical ReactionBiochemistryBiological MarkersBiological ModelsCell Culture TechniquesCellsChemicalsCitric Acid CycleClinicClinicalClinical TrialsDataDependenceDetectionDrug resistanceEffectivenessElementsGenetically Engineered MouseGlucoseGlutamatesGlutaminaseGlutamineGoalsHumanImageImmune checkpoint inhibitorImmunocompetentInstitutionKnowledgeMAP Kinase GeneMAP3K1 geneMAPK Signaling Pathway PathwayMEKsMEL GeneMagnetic Resonance ImagingMedicalMelanoma CellMetabolicMetabolic PathwayMetabolismMetastatic MelanomaMetforminMethodsModelingMonitorMusMutateMutationOxygenPathway AnalysisPathway interactionsPatientsPharmaceutical PreparationsPhenforminPhosphotransferasesPhysiologic pulseProliferatingProto-Oncogene Proteins B-rafRecurrenceResistanceSignal TransductionSignaling ProteinSystemTechniquesTimeTissue SurvivalToxic effectTranslationsTreatment ProtocolsTumor VolumeVariantWorkaerobic glycolysisanalogbaseearly detection biomarkerseffective therapyexperiencefeasibility testinghuman modelimaging modalityimmunogenicimmunosuppressedimprovedin vivoinhibitor/antagonistinstrumentkinase inhibitorliquid chromatography mass spectrometrymagnetic fieldmelanomametabolic phenotypemetabolomicsmouse modelmutantneoplastic cellnon-invasive imagingpatient responseprecision medicineresearch clinical testingresponseresponse biomarkertargeted treatmenttranslation to humanstreatment responsetumortumor growthtumor metabolismtumor microenvironment
项目摘要
Melanoma: Metabolic Biomarkers of Response to Targeted Therapy
Project Summary/Abstract
Disseminated metastatic melanoma is initially treated with inhibitors of the V600E mutated BRAF kinase, a
component of the MAPK signaling pathway that controls the replication of melanoma cells. More than half of
melanoma patients express this mutation and are at least initially responsive to its inhibition. However, all pa-
tients eventually become resistant to these inhibitors and have to be treated with alternate therapy, which con-
sists primarily of immune checkpoint inhibitors. The goal of this project is to develop an imaging method that
could monitor the effectiveness of BRAF kinase inhibitors and can promptly and accurately detect resistance to
these agents. Our strategy for achieving this goal is to study the detailed biochemical mechanism of BRAF ki-
nase signaling on the premise that a change in tumor metabolism is a quicker and more reliable indicator of the
onset of resistance than a change in tumor volume, which can require weeks to months to become reliably
manifest. We will use 13C MRS and liquid chromatography mass-spectrometry (LC-MS) to study the mecha-
nism of BRAF metabolic inhibition, but these methods are not suitable for in vivo detection in humans – 13C
MRS is not sensitive enough and LC-MS is invasive. Therefore, our strategy is to identify suitable biomarkers
of metabolic response that can be monitored by 1H MRS or MRI monitored chemical exchange saturation
transfer (CEST), which is about 500 times more sensitive than 1H MRS but requires high magnetic field instru-
ments operating at ≥ 7T. In contrast, 1H MRS can be monitored at 1.5T or 3T, for which instruments are avail-
able at many more medical institutions. Our second objective is to delineate how the biomarkers of BRAF inhi-
bition work in order to better appreciate their capabilities and limitations. Finally, preliminary data from our own
lab and from others indicates that the onset of resistance to mutant BRAF inhibitors involves a transition of the
tumor from dependence on aerobic glycolysis to substantially greater dependence on ox-phos and on glutami-
nolysis. This has led to clinical trials of the use of inhibitors of ox-phos such as metformin and phenformin to
delay the onset of resistance. As our third objective, we propose to test the feasibility of using CB-839, an in-
hibitor of glutaminase to block the transition to glutamine-dependence as a method to inhibit the onset of BRAF
resistance. Our Specific Aims are: Aim 1 will determine biochemical changes and effectiveness of MAPK
pathway inhibition in murine and human models of melanoma. Aim 2 will elucidate substrate limitations on bio-
chemical effects and biomarker response to changes in microenvironment. Aim 3 will validate the proposed
biomarkers in an in vivo system where the treatment response is modified using a glutaminase inhibitor.
Clinical Impact: This project will enable detection of melanoma response to targeted therapy by NMR meth-
ods that have already been implemented in the clinic on conventional 1.5T and 3T instruments and on 7T in-
struments that are becoming progressively more common. Metabolomic studies will expand our ability to quan-
tify tumor metabolism in cells, in mouse and human models, and eventually in humans.
黑色素瘤:对靶向治疗反应的代谢生物标志物
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ian Alexander Blair其他文献
Ian Alexander Blair的其他文献
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{{ truncateString('Ian Alexander Blair', 18)}}的其他基金
Melanoma: Metabolic Biomarkers of Response to Targeted Therapy
黑色素瘤:靶向治疗反应的代谢生物标志物
- 批准号:
10337249 - 财政年份:2020
- 资助金额:
$ 47.94万 - 项目类别:
Melanoma: Metabolic Biomarkers of Response to Targeted Therapy
黑色素瘤:靶向治疗反应的代谢生物标志物
- 批准号:
10565951 - 财政年份:2020
- 资助金额:
$ 47.94万 - 项目类别:
Analytical validation of frataxin proteoforms in blood as biomarkers of Friedreich's ataxia
血液中 frataxin 蛋白质形式作为弗里德赖希共济失调生物标志物的分析验证
- 批准号:
10356088 - 财政年份:2020
- 资助金额:
$ 47.94万 - 项目类别:
Analytical validation of frataxin proteoforms in blood as biomarkers of Friedreich's ataxia
血液中 frataxin 蛋白质形式作为弗里德赖希共济失调生物标志物的分析验证
- 批准号:
10582596 - 财政年份:2020
- 资助金额:
$ 47.94万 - 项目类别:
Analytical validation of frataxin proteoforms in blood as biomarkers of Friedreich's ataxia
血液中 frataxin 蛋白质形式作为弗里德赖希共济失调生物标志物的分析验证
- 批准号:
10117295 - 财政年份:2020
- 资助金额:
$ 47.94万 - 项目类别:
Asbestos fate, exposure, remediation, and adverse health effects
石棉的归宿、接触、修复和不良健康影响
- 批准号:
9530878 - 财政年份:2014
- 资助金额:
$ 47.94万 - 项目类别:
Asbestos fate, exposure, remediation, and adverse health effects
石棉的归宿、接触、修复和不良健康影响
- 批准号:
9041609 - 财政年份:2014
- 资助金额:
$ 47.94万 - 项目类别:
Asbestos fate, exposure, remediation, and adverse health effects
石棉的归宿、接触、修复和不良健康影响
- 批准号:
8651082 - 财政年份:2014
- 资助金额:
$ 47.94万 - 项目类别:
Development of Breast Cancer Risk Model Based on Estrogen Metabolomics
基于雌激素代谢组学的乳腺癌风险模型的开发
- 批准号:
8550778 - 财政年份:2012
- 资助金额:
$ 47.94万 - 项目类别:
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