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

• 批准号: 10659678
• 负责人: Stephen Matthew Sykes
• 金额: $ 57.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10659678
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Affect; American; Biochemical Pathway; Carbon; Catabolism; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Chemicals; Child; DNA biosynthesis; Data; Differentiation and Growth; Disease; Disease Progression; Effectiveness; Enzymes; FLT3 gene; Foundations; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genetically Engineered Mouse; Goals; Hematopoiesis; Hematopoietic Neoplasms; Human; In Vitro; Karyotype; Liposomes; LoxP-flanked allele; MLL-rearranged leukemia; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Newly Diagnosed; Non-Essential Amino Acid; Onset of illness; Outcome; Pathogenesis; Patients; Play; Positioning Attribute; Proliferating; Proteins; Proteomics; Public Health; Purines; RNA; Recurrent disease; Reporting; Resistance; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Serine; Shunt Device; Supplementation; Supporting Cell; Survival Rate; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; activating transcription factor 3; acute myeloid leukemia cell; cell growth; chemotherapy; dietary; dietary restriction; effective therapy; experimental study; improved; in vivo; inhibitor; insight; leukemia; leukemogenesis; metabolomics; mouse model; nanoparticle; novel therapeutic intervention; overexpression; patient derived xenograft model; pharmacologic; posttranscriptional; programs; protein expression; small hairpin RNA; standard of care; targeted treatment; therapeutic target; therapeutically effective; therapy resistant; transcription factor; transcriptome sequencing; transcriptomics; treatment strategy; tumor

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）： 急性髓细胞白血病（AML）是一种侵袭性血癌，目前被列为最致命的形式 成人和儿童的白血病。这些不令人满意的结果突出表明，迫切需要发展 更有效的疗法，替代或提高现有化疗的有效性。 调节非必需氨基酸丝氨酸合成和代谢的代谢途径 最近在几种不同类型的人类癌症中出现了治疗弱点。我们和其他人 最近发现，某些侵袭性AML亚型，如携带MLL重排的AML亚型， FLT 3基因的MLLR（MLLR）或内部串联重复（FLT 3 ITD）严重依赖于丝氨酸来维持细胞增殖。 循环和分化阻滞。具体来说，我们发现限制膳食丝氨酸显著延迟了 在MLLR-AML的小鼠模型中疾病发作，而其他人已经表明丝氨酸的化学抑制 合成阻碍MLLR-或FLT 3 ITD-AML。该提案旨在解决三个关键的未回答问题： 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， 提供嘌呤和嘌呤衍生物的库，如S-腺苷甲硫氨酸（SAM），这是关键的合成代谢 前体分别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组合， 患者来源的AML异种移植（PDX）模型，以精确确定丝氨酸如何用于支持AML。 2)什么丝氨酸调节酶支持AML，为什么？虽然有几种酶有助于 通过丝氨酸代谢，我们已经鉴定MTHFD 2为AML中特别重要的候选者。我们特别 已经看到MTHFD 2抑制促进MLLR-AML细胞的终末分化，此外， MTHFD 2是人类癌症中最常见的过度表达酶。我们已经获得了 我们将使用小鼠Mthfd 2的floxed等位基因来确定Mthfd 2在AML和健康人中的重要性。 造血鉴于MTHFD 2催化丝氨酸衍生碳掺入新合成的 我们还将研究Mthfd 2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，如增殖和基因表达。 3)我们能否在AML中开发有效的丝氨酸靶向疗法？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（例如同时限制膳食丝氨酸和丝氨酸 合成）或在AML的小鼠模型中使用脂质体纳米颗粒技术化学靶向MTHFD 2。 总的来说，这些研究的结果将为丝氨酸代谢的作用和 这可能为开发治疗AML的新治疗策略奠定基础。此外，委员会认为， 丝氨酸代谢通常在许多肿瘤环境中失调，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。