Targeting metabolic vulnerabilities induced by the 1p19q codeletion in oligodendrogliomas
针对少突胶质细胞瘤中 1p19q 编码缺失引起的代谢脆弱性
基本信息
- 批准号:10722255
- 负责人:
- 金额:$ 18.88万
- 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:2023-07-25 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:19q1p36AdultAnabolismAstrocytesAstrocytomaBioenergeticsBiological AssayBiological MarkersBrain NeoplasmsCancer PatientCellsCessation of lifeChemotherapy and/or radiationChromosomesCitric Acid CycleClassificationClinicClinicalCognitiveCognitive deficitsColon CarcinomaCombined Modality TherapyCompanionsCompensationDeuteriumDevelopmentDrug KineticsEnzymesGenesGenomic medicineGenomicsGliomaGlucoseGlycolysisGoalsGrowthHumanImageIsocitrate DehydrogenaseLabelLifeMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of liverMass Spectrum AnalysisMetabolicMetabolismModelingMolecularMolecular GeneticsMusMutationNeuroblastomaOncologyOutcomeOxidation-ReductionPatientsPhosphoenolpyruvatePrecision therapeuticsPrimary Brain NeoplasmsPrimatesProductionProliferatingProtein IsoformsQuality of lifeRecurrenceReportingSafetySpecificityTestingTherapeuticTranslatingTranslationsbrain tissueclinical translationclinically relevantenolasegenetic signatureglucose metabolismimaging biomarkerimaging modalityimproved outcomein vivoinhibitorinnovationmalignant breast neoplasmmetabolic imagingmetabolomicsmutantnon-invasive imagingnovelnovel therapeuticsoligodendrogliomaphosphoglycerateprecision medicinepyruvate dehydrogenaserational designresponsestandard caretreatment responsetumor
项目摘要
PROJECT SUMMARY
Gliomas are the most common malignant primary brain tumors in adults. Among gliomas driven by mutant
isocitrate dehydrogenase, tumors harboring a 1p/19q codeletion are classified as oligodendrogliomas. Current
therapies such as radiation and chemotherapy are highly toxic and cause long-lasting and life-altering deficits
in cognitive and physical abilities. Importantly, although oligodendroglioma patients live for years with standard
treatment, tumors inevitably recur and cause patient death. Since the 1p/19q codeletion is a hallmark of
oligodendrogliomas, identifying metabolic vulnerabilities associated with the 1p/19 codeletion can lead to
precision medicines for oligodendroglioma patients. Glycolytic metabolism, in particular, fuels biosynthesis and
bioenergetics and is central to tumor proliferation. The glycolytic gene enolase 1, which is located on
chromosome 1p36.23, is lost in oligodendrogliomas due to the 1p/19q codeletion, leaving these tumors
dependent on enolase 2 (ENO2) for continued glycolysis. Our studies indicate that inhibiting ENO2 using a
safe, potent ENO2 inhibitor (POMHEX) downregulates glycolysis in patient-derived oligodendrogliomas.
However, ENO2 inhibition leads to a compensatory activation of pyruvate dehydrogenase (PDH), a key
tricarboxylic acid (TCA) cycle enzyme. Importantly, combining POMHEX with the novel safe PDH inhibitor CPI-
613 completely abrogates glycolysis, the TCA cycle and oligodendroglioma growth. We will, therefore, test the
hypothesis that targeting ENO2 and PDH is a precision therapy strategy for oligodendrogliomas (Aim 1).
Successful translation of novel therapies is hindered by the lack of companion biomarkers that report on
response to therapy. Magnetic resonance imaging, which is the mainstay of glioma imaging, fails to accurately
report on response to therapy. Deuterium Magnetic Resonance Spectroscopy (DMRS) following administration
of 2H-labeled substrates such as glucose is a safe clinically translatable method of imaging glycolytic flux in
vivo. In Aim 2, we will examine the ability of 2H-glucose to report on response to ENO2 and PDH inhibition in
oligodendrogliomas in vivo at clinically relevant field strength (3T).
Our proposal is innovative and impactful because it will validate ENO2 and PDH as precision targets for
oligodendrogliomas in this era of genomic medicine. Since the safety of POMHEX and CPI-613 has been
established in primates and humans, and since DMRS can be readily deployed on clinical MR scanners, our
therapies and companion biomarkers have the potential to be rapidly translated to the clinic. In essence, by
simultaneously targeting metabolism for therapy and for imaging treatment response, our studies will enable
precision medicine that improves outcomes and quality of life for oligodendroglioma patients.
项目总结
项目成果
期刊论文数量(0)
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