The role of glutaminolysis as a therapeutic target in T-ALL
The role of glutaminolysis as a therapeutic target in T-ALL
批准号:
10412085
负责人:
Daniel Herranz
金额:
$36.37万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-01 至 2023-06-30
关键词:
Acute T Cell LeukemiaAddressAdultAftercareAreaAttentionAutomobile DrivingAutophagocytosisCRISPR/Cas technologyCarbonCell LineCellsChemotherapy-Oncologic ProcedureChildChildhoodCitric Acid CycleClinicalClinical TreatmentClinical TrialsCombined Modality TherapyCritical PathwaysDataDetectionDevelopmentDiseaseEpigenetic ProcessGene Expression ProfilingGenerationsGenesGeneticGenetic TranscriptionGlucoseGlutaminaseGlutamineGoalsHematologic NeoplasmsHematologyHematopoieticHematopoietic stem cellsHumanIn VitroInfusion proceduresInvestigational TherapiesLabelLeadLeukemic CellLightMalignant NeoplasmsMapsMediatingMetabolicMetabolic PathwayMetabolismMusMutationNOTCH1 geneOncogenesPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPlayPrognosisProto-Oncogene Proteins c-aktRefractoryRefractory DiseaseRelapseResearchResearch ProposalsResistanceRoleRouteSignal TransductionSolid NeoplasmTherapeuticTherapeutic EffectToxic effectValidationacute lymphoblastic leukemia cellcancer cellcancer stem cellcancer typecell growthconditional knockoutexhaustionexperimental studygamma secretasehexokinaseimprovedin vivoinhibitorleukemianew therapeutic targetnovelpatient derived xenograft modelrational designresponseself-renewalstem cellsstemnesstargeted treatmenttherapeutic targettooltumor metabolism
中文摘要
摘要:
--
人类癌症研究的一个关键标志是癌症特异性代谢基因的重新连接。值得注意的是,这一关键领域的研究已经取得了进展。
在过去十年中,在几项新的研究证明关键的癌基因在人类癌症中起作用后,人们重新引起了人们的关注。
如AKT、KRAS、MYC或NOTCH1,它们对原发细胞的代谢有不同的影响和特定的影响。
这导致了一种新的假设,即选择性地针对这些路线中的一条可能是一种非常有吸引力的治疗性治疗方法。
在这种背景下,我最近发现,谷氨酰胺溶解是NOTCH1驱动的急性T细胞谱系中的一种关键途径。
淋巴母细胞性白血病(T-ALL)是一种常见的血液学和恶性肿瘤,在高达20%的儿童中发生复发。
50%的成年癌症患者最终死于一种难治性疾病。更重要的是,对谷氨酰胺溶解的抑制作用。
从遗传学上讲,通过删除谷氨酰胺酶(GLS),或者从药理上讲,通过使用谷氨酰胺酶抑制剂,可以获得更好的抗白血病效果。
Effect And与其他抗NOTCH1药物疗法高度协同。值得注意的是,GLS药物选择性药物目前还在研发中。
用于治疗血液病、恶性肿瘤和谷氨酰胺溶解症的临床试验中探索的药物也已被建议作为一种治疗方法。
然而,谷氨酰胺在体内肿瘤中的重要作用仍未得到很好的了解。
而GLS缺陷的TALL最终也不会取得进展,这突显出我们需要更多地了解这些问题的机制。
旧病复发。我的初步数据显示,谷氨酰胺衍生的碳排放可能不会进入新的TCA循环和GLS--
有缺陷的T-all可能仍然不会使用谷氨酰胺,即使在谷氨酰胺酶几乎没有的情况下也是如此。此外,这是我的初步研究数据。
指出谷氨酰胺酶在植物茎化中的重要作用。因此,这项研究和建议旨在:1)剖析谷氨酰胺酶在植物茎中的作用。
谷氨酰胺酶在活体动物中的作用,并揭开了人类逃脱的主要机制;;(2)将解决的主要作用。
谷氨酰胺分解与茎干有关;;1和3)将识别具有药理作用和抑制作用的合成的致死途径/基因。
应用CRIPSR/Cas9对谷氨酰胺酶基因缺失的谷氨酰胺酶进行体外筛选和实验。
治疗药物的实验正在体内进行。这些研究将进一步揭示尚未发现的基本治疗机制。
牵涉到T-ALL的主要代谢过程和表观遗传学改变,这将有助于我们更好地理解GLS的主要作用。
而谷氨酰胺分解作用在癌症、癌症和癌症中的作用将有助于我们理性地设计一种新的代谢物或表观遗传学靶向的组合。
治疗方法认为,这将导致更强的治疗效果,并降低复发的可能性。
英文摘要
ABSTRACT
A key hallmark of human cancer is cancer-specific metabolic rewiring. Notably, this area of research has gained
renewed attention in the last decade after several studies demonstrated that key oncogenes in human cancer,
such as AKT, KRas, MYC or NOTCH1, have differential and specific effects on primary cellular metabolism,
leading to the hypothesis that selective targeting of those routes might be an attractive therapeutic approach. In
this context, I recently identified glutaminolysis as a critical pathway in NOTCH1-driven T-lineage acute
lymphoblastic leukemia (T-ALL), a hematological malignancy where relapses occur in up to 20% of pediatric
and 50% of adult patients, who ultimately succumb to refractory disease. Importantly, inhibition of glutaminolysis
genetically, via deletion of glutaminase (Gls), or pharmacologically, using Gls inhibitors, results in anti-leukemic
effects and is highly synergistic with anti-NOTCH1 therapies. Notably, Gls selective inhibitors are currently being
explored in clinical trials for hematological malignancies, and glutaminolysis has also been proposed as a
therapeutic target in a variety of solid tumors. However, the role of glutamine in vivo is still not well understood
and Gls-deficient T-ALLs eventually progress, underscoring the need to understand the mechanisms of
relapse. My preliminary data suggests that glutamine-derived carbon might feed into the TCA cycle and Gls-
deficient T-ALLs might still use glutamine even in the absence of glutaminase. Moreover, my preliminary data
points to a role of glutaminase in stemness. Therefore, this research proposal seeks to: 1) dissect the role of
glutaminase in T-ALL in vivo and unravel the mechanisms of escape to Gls loss;; 2) address the role of
glutaminolysis in stemness;; and 3) identify synthetic lethal pathways/genes with pharmacological inhibition of
glutaminase or with genetic loss of glutaminase using CRIPSR/Cas9 screens in vitro and experimental
therapeutic experiments in vivo. These studies will reveal as yet undiscovered fundamental mechanisms
implicated in the metabolic and epigenetic rewiring of T-ALL, will advance our understanding of the role of Gls
and glutaminolysis in cancer, and will help us rationally design combinations of metabolic or epigenetic targeted
therapies that will result in stronger therapeutic effects with decreased chances of relapse.
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The role of glutaminolysis as a therapeutic target in T-ALL
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批准号:10663181
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项目类别:
-
资助金额:$35.64万
-
财政年份:2019
-
负责人:Daniel Herranz
-
依托单位:
The role of glutaminolysis as a therapeutic target in T-ALL
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批准号:10197854
-
项目类别:
-
资助金额:$36.37万
-
财政年份:2019
-
负责人:Daniel Herranz
-
依托单位:
Functional dissection of oncogenic enhancers
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批准号:9111911
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项目类别:
-
资助金额:$17.09万
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财政年份:2015
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负责人:Daniel Herranz
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依托单位:
海外基金