Targeting Cysteine Susceptibility in Glioblastoma
靶向胶质母细胞瘤中的半胱氨酸敏感性
基本信息
- 批准号:10818812
- 负责人:
- 金额:$ 3.4万
- 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:2022-09-01 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcysteineAdvisory CommitteesAmino AcidsAnimal ModelAntibioticsBiological MarkersBiologyBlood GlucoseCarbohydratesCeftriaxoneCell DeathCell LineCellsChemotherapy and/or radiationClinical TrialsCombined Modality TherapyCysteineCysteine Metabolism PathwayCystineDataDependenceDevelopment PlansDietDrug Metabolic DetoxicationEffectivenessElectron TransportEnvironmentExhibitsFoundationsFundingFutureGene ExpressionGlioblastomaGliomaGlucoseGlutamatesGlutathioneGoalsGrowthHomocysteineHumanHydrogen PeroxideHypoglycemic AgentsHypoxiaImageInstitutionInternationalInterventionInvestmentsJunior PhysicianMalignant NeoplasmsMeasuresMediatingMedicineMentorsMentorshipMetabolicMetabolic PathwayMetabolismMethionine Metabolism PathwayMitochondriaMusNADPNeurologyNormal tissue morphologyOncologistOxidation-ReductionOxidative StressPathway interactionsPatientsPentosephosphate PathwayPharmaceutical PreparationsPharmacotherapyPhasePhysiciansPositron-Emission TomographyPre-Clinical ModelPredispositionProductionPyruvateRadiationReactive Oxygen SpeciesReducing dietResearchResearch PersonnelRoleScienceScientistSecureStressSystemTestingThe Cancer Genome AtlasToxic effectTrainingTransgenic OrganismsTranslatingTranslationsTreatment EfficacyTumor EscapeTumor TissueUnited States National Institutes of HealthUp-RegulationWorkXenograft procedurecancer cellcareercareer developmentclinical developmentcombinatorialcytotoxiccytotoxicitydeprivationearly phase clinical trialefficacy testingenzyme activityextracellularglioma cell lineglucose metabolismglucose uptakeimprovedin vivoketogenic dietketogenticluciferinmetabolomicsmolecular imagingmouse modelneoplastic cellneuro-oncologyneurotoxicitynovelnovel therapeutic interventionpharmacologicpre-clinicalprecision medicineprofessorresponseskillssynergismtemozolomidetranslational approachtumortumor metabolismuptake
项目摘要
Project Abstract
Glioblastoma (GBM) is one of the most lethal human cancers. Standard GBM treatments, such as radiation
(RT) and temozolomide (TMZ), exhibit poor efficacy with a lack of a durable response. These agents promote
oxidative stress in cancer cells, which is a known metabolic liability of GBM. However, the efficacy of these
treatments is limited by neurotoxicity and upregulation of tumor escape pathways that detoxify reactive oxygen
species. There is an urgent need for new pharmacological agents that effectively target the redox stress
pathway in GBM cells while sparing adjacent normal tissue. My long-term goal is to become an independent
physician-scientist neuro-oncologist focused on improving GBM therapy. In this proposal, I use my discovery
of a cysteine susceptibility pathway in glioma, whereby cysteine-promoting compounds induce glucose
dependence, mitochondrial toxicity, and H2O2 production, to define the mechanism and functional relevance
of this pathway in pre-clinical models. I will test the central hypothesis that high levels of intracellular cysteine
induce glucose dependence in glioma, and the combination of cysteine compounds with ROS-promoting
treatments is an effective strategy to improve survival in mouse models of GBM. I will identify the metabolic
flux pathways altered by cysteine in glioma (Aim 1a) and determine the role of mitochondrial electron transport
chain flux (Aim 1b) and hypoxia and glycolytic flux (Aim 1c) in contributing to cysteine-mediated glucose
dependence. Using mouse models of GBM, I will test the efficacy of cysteine compounds in combination with
ROS-promoting interventions (RT, TMZ, and the glucose-lowering ketogenic diet) on GBM metabolism, growth,
and survival, using 18F-fluoropropyl-homocysteine positron emission tomography as a biomarker for cysteine
metabolism (Aim 2a). I will determine the effects of H2O2 modulation on cytotoxicity of cysteine compounds
and ROS-promoting interventions (Aim 2b) in vivo. These aims will create a new paradigm that uses two
synergistic metabolic therapies that can be rapidly translated into early-phase clinical trials in GBM. I am an
Assistant Professor in Neurology within the Division of Neuro-Oncology at Weill Cornell Medicine (WCM), and
I have outlined a 5-year plan that expands on my background studying GBM metabolism. I have an outstanding
mentor, Dr. Lewis Cantley, who is an expert in tumor metabolism and has enabled translation of his work and
mentees’ work to clinical development. My career advisory committee includes Drs. Lewis Cantley (primary
mentor), Navdeep Chandel, Pedro Lowenstein, Naga Vara Kishore Pillarsetty, Howard Fine, and Matthew
Fink. They are internationally recognized experts in science and medicine and will provide mentorship and
support to attain scientific independence. I will also have unparalleled institutional support from WCM, which
is at the forefront of precision medicine in cancer and is heavily invested in career development for junior
physician-scientists. This research and training environment will enable me to achieve my goals of securing
NIH R01 funding in the future.
1
项目摘要
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Evan K. Noch其他文献
Evaluating factors impacting early career physician-scientists’ decisions to continue research careers in the United States of America
- DOI:
10.1186/s12909-025-07144-4 - 发表时间:
2025-04-17 - 期刊:
- 影响因子:3.200
- 作者:
Kassem Farhat;Aleksandar Obradovic;Aisha Siebert;Han Naung Tun;Evan K. Noch;Jennifer M. Kwan - 通讯作者:
Jennifer M. Kwan
Correction: Evaluating factors impacting early career physician-scientists’ decisions to continue research careers in the United States of America
- DOI:
10.1186/s12909-025-07275-8 - 发表时间:
2025-05-09 - 期刊:
- 影响因子:3.200
- 作者:
Kassem Farhat;Aleksandar Obradovic;Aisha Siebert;Han Naung Tun;Evan K. Noch;Jennifer M. Kwan - 通讯作者:
Jennifer M. Kwan
Evan K. Noch的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Evan K. Noch', 18)}}的其他基金
Targeting cysteine susceptibility in glioblastoma
靶向胶质母细胞瘤中的半胱氨酸敏感性
- 批准号:
10507157 - 财政年份:2022
- 资助金额:
$ 3.4万 - 项目类别:
相似海外基金
Toward a Political Theory of Bioethics: Participation, Representation, and Deliberation on Federal Bioethics Advisory Committees
迈向生命伦理学的政治理论:联邦生命伦理学咨询委员会的参与、代表和审议
- 批准号:
0451289 - 财政年份:2005
- 资助金额:
$ 3.4万 - 项目类别:
Standard Grant