Exploiting Pyrimidine Nucleotide Synthesis Dependence for IDH Mutant Glioma Therapy
利用嘧啶核苷酸合成依赖性进行 IDH 突变胶质瘤治疗
基本信息
- 批准号:10609088
- 负责人:
- 金额:$ 36.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-07 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AchievementAddressAdult GliomaAnabolismApoptosisBiologicalBiological MarkersBrainBrain NeoplasmsBranched-Chain Amino AcidsCatabolismCell DeathCell SurvivalCellsCentral Nervous System NeoplasmsChemicalsChromatin StructureClinicClinicalClinical TrialsCoupledDNA biosynthesisDefectDependenceDihydroorotate Dehydrogenase InhibitorDihydroorotate dehydrogenaseDiseaseDisease modelDrug TargetingEndoplasmic ReticulumEnzyme Inhibitor DrugsEnzymesFDA approvedFoundationsFunctional disorderFutureGene ExpressionGene SilencingGenesGeneticGenetic HeterogeneityGlioblastomaGliomaGlutaminaseGlutamineGoalsHomeostasisHumanImpairmentIndividualIsocitrate DehydrogenaseLipidsMalignant - descriptorMalignant NeoplasmsMedicalMetabolicMetabolic PathwayMetabolismModelingMolecularMutateMutationNewly DiagnosedOncoproteinsOrganoidsPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhospholipidsPre-Clinical ModelPredispositionPrimary Brain NeoplasmsProductionProtein GlycosylationProteinsPyrimidinePyrimidine NucleotidesPyrimidine Synthesis InhibitionRNA chemical synthesisRadiation therapyResearchResistanceRoleStressSurveysSurvival RateSystemTestingTherapeuticTissuesTranslatingTumor Cell LineUnited StatesWorkcancer therapyclinical translationcombatdesignefficacy evaluationendoplasmic reticulum stressexperimental studygain of functionglioma cell linein vivoinhibitorinhibitor therapymouse modelmutantneoplastic cellnovelnovel therapeutic interventionnovel therapeuticsnucleotide metabolismpatient derived xenograft modelpre-clinicalpreclinical trialpredicting responsepredictive markerresearch clinical testingresponsestandard caresuccesstreatment responsetreatment strategytumortumor growthtumor microenvironment
项目摘要
PROJECT SUMMARY
Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system
tumors in the United States each year and are among the most lethal and treatment-resistant human cancers.
Although there is a dire need for new ways to combat this disease, the standard treatment for gliomas has not
changed since 2005 and no new glioma medical therapies have been approved in the last decade. In response
to this challenge, we have devised a new way to treat gliomas that have a mutation in a gene called IDH1. IDH1
mutations are present in 70-90% of lower grade gliomas and secondary glioblastomas, a highly aggressive
subtype of glioma. We surveyed hundreds of drugs and discovered that a class of drugs that inhibit a particular
metabolic pathway preferentially killed brain tumor cells with IDH1 mutations. Our proposal builds on this
discovery by addressing three Specific Aims. Specific Aim #1 is to understand the molecular mechanisms
through which IDH1 mutations increase sensitivity to inhibitors of this metabolic pathway. We will use cultured
brain tumor cell lines that harbor or lack IDH1 mutations to test our hypothesis that the combined effects of IDH1
mutations and these inhibitors severely impair protein processing and lipid production in tumor cells, creating
stress that ultimately triggers cell death. Specific Aim #2 is to use organoid models derived from human glioma
tissue to assess whether the presence of an IDH1 mutation successfully predicts response to inhibitors of the
metabolic pathway we propose targeting. Organoids represent powerful preclinical disease models because they
allow us to test new therapeutic strategies in a cellular system that accurately reflects the makeup of human
brain tumors. Specific Aim #3 is to use a mouse model of glioma to assess whether inhibiting the metabolic
pathway we've identified to be important for IDH1 mutant brain tumor cells leads to desirable therapeutic
responses, including a block in tumor growth and extension of host survival. These studies will clarify whether
targeting this pathway is likely to provide benefit for human patients with IDH1 mutated brain tumors. Taken
together, our work will outline and test a new treatment strategy for brain tumor patients that could be rapidly
translated to the clinic if our studies are successful. Furthermore, our efforts may demonstrate that IDH1
mutations can be used to faithfully identify individuals whose tumors are poised to respond to the treatment
strategy we are developing, thereby providing a way to design potential future clinical trials that have the greatest
chance to provide benefit for glioma patients.
项目概要
神经胶质瘤占新诊断的 26,000 例脑部和中枢神经系统恶性病例的 80%
肿瘤每年在美国发生,并且是最致命和最难治疗的人类癌症之一。
尽管迫切需要新的方法来对抗这种疾病,但神经胶质瘤的标准治疗方法还没有
自 2005 年以来发生了变化,并且在过去十年中没有新的神经胶质瘤药物疗法获得批准。作为回应
为了应对这一挑战,我们设计了一种新方法来治疗 IDH1 基因突变的神经胶质瘤。 IDH1
70-90% 的低级别胶质瘤和继发性胶质母细胞瘤中存在突变,这是一种高度侵袭性的肿瘤
神经胶质瘤的亚型。我们调查了数百种药物,发现一类药物可以抑制特定的药物
代谢途径优先杀死具有 IDH1 突变的脑肿瘤细胞。我们的建议建立在这个基础上
通过解决三个具体目标来发现。具体目标#1是了解分子机制
IDH1 突变可增加对该代谢途径抑制剂的敏感性。我们将用有文化的
携带或缺乏 IDH1 突变的脑肿瘤细胞系来检验我们的假设,即 IDH1 的综合作用
突变和这些抑制剂严重损害肿瘤细胞中的蛋白质加工和脂质产生,从而产生
最终引发细胞死亡的压力。具体目标#2是使用源自人类神经胶质瘤的类器官模型
组织来评估 IDH1 突变的存在是否成功预测对抑制剂的反应
我们建议针对的代谢途径。类器官代表了强大的临床前疾病模型,因为它们
使我们能够在准确反映人类构成的细胞系统中测试新的治疗策略
脑肿瘤。具体目标#3是使用神经胶质瘤小鼠模型来评估是否抑制代谢
我们已经确定对 IDH1 突变脑肿瘤细胞很重要的途径可导致理想的治疗
反应,包括阻止肿瘤生长和延长宿主生存。这些研究将澄清是否
针对这一途径可能会给患有 IDH1 突变脑肿瘤的人类患者带来益处。采取
我们的工作将共同概述并测试一种针对脑肿瘤患者的新治疗策略,该策略可以快速实现
如果我们的研究成功的话,就会转化为临床。此外,我们的努力可能表明 IDH1
突变可用于忠实地识别肿瘤对治疗有反应的个体
我们正在开发的策略,从而提供了一种设计潜在的未来临床试验的方法,这些试验具有最大的
有机会为神经胶质瘤患者带来好处。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Emerging roles of nucleotide metabolism in cancer.
核苷酸代谢在癌症中的新作用。
- DOI:10.1016/j.trecan.2023.04.008
- 发表时间:2023
- 期刊:
- 影响因子:18.4
- 作者:Shi,DianaD;Savani,MilanR;Abdullah,KalilG;McBrayer,SamuelK
- 通讯作者:McBrayer,SamuelK
Isocitrate dehydrogenase mutations in gliomas: A review of current understanding and trials.
- DOI:10.1093/noajnl/vdad053
- 发表时间:2023-01
- 期刊:
- 影响因子:0
- 作者:Sharma, Nikhil;Mallela, Arka N.;Shi, Diana D.;Tang, Lilly W.;Abou-Al-Shaar, Hussam;Gersey, Zachary C.;Zhang, Xiaoran;McBrayer, Samuel K.;Abdullah, Kalil G.
- 通讯作者:Abdullah, Kalil G.
Preclinical modeling of lower-grade gliomas.
- DOI:10.3389/fonc.2023.1139383
- 发表时间:2023
- 期刊:
- 影响因子:4.7
- 作者:Tang LW;Mallela AN;Deng H;Richardson TE;Hervey-Jumper SL;McBrayer SK;Abdullah KG
- 通讯作者:Abdullah KG
Semi-Automated Computational Assessment of Cancer Organoid Viability Using Rapid Live-Cell Microscopy.
- DOI:10.1177/11769351221100754
- 发表时间:2022
- 期刊:
- 影响因子:2
- 作者:Buehler, Joseph D.;Bird, Cylaina E.;Savani, Milan R.;Gattie, Lauren C.;Hicks, William H.;Levitt, Michael M.;El Shami, Mohamad;Hatanpaa, Kimmo J.;Richardson, Timothy E.;McBrayer, Samuel K.;Abdullah, Kalil G.
- 通讯作者:Abdullah, Kalil G.
A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma.
- DOI:10.1016/j.ccell.2022.07.012
- 发表时间:2022-09-12
- 期刊:
- 影响因子:50.3
- 作者:Pal, Sharmistha;Kaplan, Jakub P.;Nguyen, Huy;Stopka, Sylwia A.;Savani, Milan R.;Regan, Michael S.;Nguyen, Quang-De;Jones, Kristen L.;Moreau, Lisa A.;Peng, Jingyu;Dipiazza, Marina G.;Perciaccante, Andrew J.;Zhu, Xiaoting;Hunsel, Bradley R.;Liu, Kevin X.;Alexandrescu, Sanda;Drissi, Rachid;Filbin, Mariella G.;McBrayer, Samuel K.;Agar, Nathalie Y. R.;Chowdhury, Dipanjan;Haas-Kogan, Daphne A.
- 通讯作者:Haas-Kogan, Daphne A.
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{{ truncateString('Kalil G Abdullah', 18)}}的其他基金
Exploiting Pyrimidine Nucleotide Synthesis Dependence for IDH Mutant Glioma Therapy
利用嘧啶核苷酸合成依赖性进行 IDH 突变胶质瘤治疗
- 批准号:
10180738 - 财政年份:2021
- 资助金额:
$ 36.76万 - 项目类别:
Exploiting Pyrimidine Nucleotide Synthesis Dependence for IDH Mutant Glioma Therapy
利用嘧啶核苷酸合成依赖性进行 IDH 突变胶质瘤治疗
- 批准号:
10402879 - 财政年份:2021
- 资助金额:
$ 36.76万 - 项目类别:
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