Determining the Role and Targeting potential of Serine Metabolism in aggressive sub-types of Acute Myeloid Leukemia
确定丝氨酸代谢在急性髓系白血病侵袭性亚型中的作用和靶向潜力
基本信息
- 批准号:10659678
- 负责人:
- 金额:$ 57.57万
- 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:2023-03-01 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAddressAdultAffectAmericanBiochemical PathwayCarbonCatabolismCell CycleCell Differentiation processCell ProliferationCell physiologyCellsChemicalsChildDNA biosynthesisDataDifferentiation and GrowthDiseaseDisease ProgressionEffectivenessEnzymesFLT3 geneFoundationsGene ExpressionGene Expression RegulationGenetic TranscriptionGenetically Engineered MouseGoalsHematopoiesisHematopoietic NeoplasmsHumanIn VitroKaryotypeLiposomesLoxP-flanked alleleMLL-rearranged leukemiaMalignant NeoplasmsMass Spectrum AnalysisMediatingMetabolicMetabolic PathwayMetabolismModelingMolecularMusNewly DiagnosedNon-Essential Amino AcidOnset of illnessOutcomePathogenesisPatientsPlayPositioning AttributeProliferatingProteinsProteomicsPublic HealthPurinesRNARecurrent diseaseReportingResistanceRoleS-AdenosylhomocysteineS-AdenosylmethionineSerineShunt DeviceSupplementationSupporting CellSurvival RateTechnologyTestingTherapeuticTherapeutic InterventionTissuesWorkactivating transcription factor 3acute myeloid leukemia cellcell growthchemotherapydietarydietary restrictioneffective therapyexperimental studyimprovedin vivoinhibitorinsightleukemialeukemogenesismetabolomicsmouse modelnanoparticlenovel therapeutic interventionoverexpressionpatient derived xenograft modelpharmacologicposttranscriptionalprogramsprotein expressionsmall hairpin RNAstandard of caretargeted treatmenttherapeutic targettherapeutically effectivetherapy resistanttranscription factortranscriptome sequencingtranscriptomicstreatment strategytumor
项目摘要
Project Summary/Abstract (30 lines max):
Acute myeloid leukemia (AML) is an aggressive blood cancer that currently ranks as the deadliest form
of leukemia in both adults and children. These unsatisfactory outcomes highlight the urgent need to develop
more-effective therapies that either replace or improve the effectiveness existing chemotherapies.
Metabolic pathways that regulate the synthesis and catabolism of the non-essential amino acid, serine
have recently emerged as therapeutic vulnerabilities in several different types of human cancer. We and others
recently discovered that certain aggressive sub-types of AML, such as those bearing MLL-rearrangements
(MLLR) or internal tandem duplications of the FLT3 genes (FLT3ITD) heavily depend on serine to maintain cell
cycling and the differentiation blockade. Specifically, we found that restriction of dietary serine significantly delays
disease onset in a mouse model of MLLR-AML, while others have shown that chemical inhibition of serine
synthesis impedes MLLR- or FLT3ITD-AML. This proposal aims to address 3 key unanswered questions:
1) How is serine utilized to support AML? Our preliminary data suggest that AML cells utilize serine to
supply pools of purines and purine-derivatives such as S-adenosylmethionine (SAM), which are key anabolic
precursors needed to drive cell proliferation and maintain gene expression programs, respectively. We will use
a combination of metabolomics, transcriptomics and proteomics in genetically engineered mouse (GEM) and
patient-derived xenograft (PDX) models of AML to precisely determine how serine is utilized to support AML.
2) What serine-regulatory enzymes support AML and why? Although several enzymes contribute to
serine metabolism, we have identified MTHFD2 as a particularly important candidate in AML. Specifically, we
have seen that MTHFD2 inhibition promotes the terminal differentiation of MLLR-AML cells and furthermore,
MTHFD2 is the most frequently over-expressed enzyme in human cancer. We have now obtained mice bearing
floxed alleles of murine Mthfd2, which we will use to determine the importance of Mthfd2 in AML and healthy
hematopoiesis. Given that MTHFD2 catalyzes the incorporation of serine-derived carbons into newly synthesized
purines and SAM, we will also examine how Mthfd2 deletion impacts purine and SAM levels as well as the
downstream cellular processes supported by these metabolites, such as proliferation and gene expression.
3) Can we develop effective serine-targeting therapies in AML? To address this question, we will evaluate
therapeutic strategies for limiting serine availability (e.g. simultaneously restricting dietary serine and serine
synthesis) or chemically targeting MTHFD2 using liposomal nanoparticle technology in mouse models of AML.
Collectively, the results of these studies will provide new insights into the role of serine metabolism and
potentially establish a foundation for developing novel therapeutic strategies for the treatment of AML. Moreover,
serine metabolism is often deregulated in many tumor settings and thus results from our proposed studies will
likely have implications for other forms of human cancers.
项目摘要/摘要(最多 30 行):
急性髓系白血病 (AML) 是一种侵袭性血癌,目前被列为最致命的癌症形式
成人和儿童的白血病。这些令人不满意的结果凸显了发展的迫切需要
更有效的疗法可以替代现有化疗或提高现有化疗的有效性。
调节非必需氨基酸丝氨酸的合成和分解代谢的代谢途径
最近出现了几种不同类型人类癌症的治疗漏洞。我们和其他人
最近发现 AML 的某些侵袭性亚型,例如带有 MLL 重排的亚型
(MLLR) 或 FLT3 基因的内部串联重复 (FLT3ITD) 严重依赖丝氨酸来维持细胞
循环和分化封锁。具体来说,我们发现限制饮食丝氨酸会显着延迟
MLLR-AML 小鼠模型中的疾病发作,而其他人则表明丝氨酸的化学抑制
合成阻碍 MLLR-或 FLT3ITD-AML。该提案旨在解决 3 个尚未解答的关键问题:
1) 丝氨酸如何用于支持 AML?我们的初步数据表明 AML 细胞利用丝氨酸
嘌呤和嘌呤衍生物的供应库,例如 S-腺苷甲硫氨酸 (SAM),它们是合成代谢的关键
分别需要驱动细胞增殖和维持基因表达程序。我们将使用
基因工程小鼠 (GEM) 中代谢组学、转录组学和蛋白质组学的结合
AML 患者来源的异种移植 (PDX) 模型,用于精确确定如何利用丝氨酸来支持 AML。
2) 哪些丝氨酸调节酶支持 AML?为什么?尽管有几种酶有助于
丝氨酸代谢,我们已经确定 MTHFD2 是 AML 中特别重要的候选者。具体来说,我们
已经发现 MTHFD2 抑制促进 MLLR-AML 细胞的终末分化,而且,
MTHFD2 是人类癌症中最常过度表达的酶。我们现在已经获得了小鼠轴承
小鼠 Mthfd2 的 floxed 等位基因,我们将用它来确定 Mthfd2 在 AML 和健康中的重要性
造血作用。鉴于 MTHFD2 催化丝氨酸衍生碳并入新合成的
嘌呤和 SAM,我们还将研究 Mthfd2 缺失如何影响嘌呤和 SAM 水平以及
这些代谢物支持的下游细胞过程,例如增殖和基因表达。
3) 我们能否开发出有效的 AML 丝氨酸靶向疗法?为了解决这个问题,我们将评估
限制丝氨酸可用性的治疗策略(例如同时限制饮食丝氨酸和丝氨酸
合成)或在 AML 小鼠模型中使用脂质体纳米颗粒技术化学靶向 MTHFD2。
总的来说,这些研究的结果将为丝氨酸代谢和丝氨酸代谢的作用提供新的见解。
可能为开发治疗 AML 的新治疗策略奠定基础。而且,
丝氨酸代谢在许多肿瘤环境中经常失调,因此我们提出的研究结果将
可能对其他形式的人类癌症有影响。
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)
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Stephen Matthew Sykes其他文献
Stephen Matthew Sykes的其他文献
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{{ truncateString('Stephen Matthew Sykes', 18)}}的其他基金
Targeting the Unfolded Protein Response in Leukemia Biology and Chemotherapy Resistance
靶向白血病生物学和化疗耐药中未折叠的蛋白质反应
- 批准号:
9927608 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Targeting the Unfolded Protein Response in Leukemia Biology and Chemotherapy Resistance
靶向白血病生物学和化疗耐药中未折叠的蛋白质反应
- 批准号:
10620629 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Targeting the Unfolded Protein Response in Leukemia Biology and Chemotherapy Resistance
靶向白血病生物学和化疗耐药中未折叠的蛋白质反应
- 批准号:
10395497 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Foxo transcription factors are required for maintenance of acute myeloid leukemia
Foxo 转录因子是维持急性髓系白血病所必需的
- 批准号:
8526748 - 财政年份:2012
- 资助金额:
$ 57.57万 - 项目类别:
Foxo transcription factors are required for maintenance of acute myeloid leukemia
Foxo 转录因子是维持急性髓系白血病所必需的
- 批准号:
8551381 - 财政年份:2012
- 资助金额:
$ 57.57万 - 项目类别:
Foxo transcription factors are required for maintenance of acute myeloid leukemia
Foxo 转录因子是维持急性髓系白血病所必需的
- 批准号:
8300569 - 财政年份:2012
- 资助金额:
$ 57.57万 - 项目类别:
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