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
人类癌症的一个关键标志是癌症特异性代谢重新布线。值得注意的是,这一研究领域已经获得了
在过去的十年中,在几项研究表明人类癌症中的关键癌基因,
例如AKT、KRas、MYC或NOTCH 1,对初级细胞代谢具有不同的和特异性的作用,
这导致了这样的假设,即选择性靶向这些途径可能是一种有吸引力的治疗方法。在
在这种背景下,我最近发现,在NOTCH 1-β驱动的T细胞系急性炎症反应中,
淋巴母细胞白血病(T-ALL)是一种血液恶性肿瘤,在儿童中复发率高达20%。
50%的成年患者最终死于难治性疾病。重要的是,抑制多巴胺分解
在遗传学上,通过使用Gls抑制剂缺失转氨酶(Gls)或GST,
作用,并且与抗HIV-NOTCH 1疗法高度协同。值得注意的是,Gls选择性抑制剂目前正在被研究。
在血液恶性肿瘤的临床试验中进行了探索,并提出了氨解作为一种治疗方法。
在各种实体瘤中的治疗靶点。然而,谷氨酰胺在体内的作用仍不清楚
和Gls-β缺陷的T细胞ALL最终进展,强调需要了解的机制,
复发 我的初步数据表明,谷氨酰胺衍生的碳可能会进入TCA循环和Gls-β。
缺陷型T细胞ALL即使在缺乏谷氨酰胺酶的情况下仍可能使用谷氨酰胺。 此外,我的初步数据
表明了转氨酶在干性中的作用。 因此,本研究建议:1)剖析
在体内T-ALL中的谷氨酰胺酶,并解开逃逸到Gls损失的机制;
干性中的氨解; 3)鉴定具有药理学抑制的合成致死途径/基因,
在体外和实验中使用CRIPSR/Cas9筛选具有转氨酶或具有转氨酶的遗传缺失的人
体内治疗实验。 这些研究将揭示尚未发现的基本机制
与T-ALL的代谢和表观遗传重新连接有关,将促进我们对Gls作用的理解。
以及癌症中的氨解,并将帮助我们合理设计代谢或表观遗传靶向治疗的组合。
这些疗法将产生更强的治疗效果,减少复发的机会。
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: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:
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
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财政年份:2019
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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