Enhancing TET activity for the treatment of hematological malignancy

增强 TET 活性治疗血液恶性肿瘤

• 批准号: 10717715
• 负责人: Luisa Cimmino
• 金额: $ 35.11万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717715
• 关键词: Acute Myelocytic Leukemia; Adjuvant; Adjuvant Therapy; Adult; Adult Acute Myeloblastic Leukemia; Adverse effects; Age Years; Aggressive behavior; Alleles; Animal Model; Antineoplastic Agents; Antioxidants; Ascorbic Acid; Biological Assay; Biological Availability; Bone Marrow Transplantation; Cell Line; Cell model; Chemicals; Chemistry; Combined Modality Therapy; DNA; Data; Dedications; Dependence; Diagnosis; Disease; Dose; Drug Combinations; Drug Kinetics; Elderly; Elderly Acute Myeloblastic Leukemia; Enzymes; Foundations; Gene Expression; Gene Silencing; Genetic; Genetic Screening; Goals; Growth; Hematologic Neoplasms; Hematopoietic; Heterozygote; Human; Hypermethylation; Impairment; Infusion procedures; Lesion; Leukemic Cell; Libraries; Liposomes; Measures; Mediating; Micronutrients; Modeling; Molecular; Mus; Mutation; Myeloid Cells; Oncogenic; Patients; Physiological; Prognosis; Property; Proteins; Research; Residual state; Role; Sodium; Surface; Testing; Tetanus Helper Peptide; Therapeutic; Therapeutic Agents; Treatment Efficacy; Treatment outcome; Tumor Suppressor Proteins; Water; Xenograft procedure; acute myeloid leukemia cell; alternative treatment; analog; aqueous; ascorbate; cancer cell; chemotherapy; clinical translation; cofactor; combinatorial; demethylation; epigenome; functional restoration; improved; in vivo; leukemia; leukemia treatment; lipophilicity; loss of function; loss of function mutation; mouse model; mutant; novel; novel strategies; oxidation; patient subsets; pharmacologic; preclinical efficacy; programs; rational design; screening; self-renewal; synergism; targeted treatment; therapeutically effective; treatment response; treatment strategy; tumor; uptake

PROJECT SUMMARY Advanced age in the majority of acute myeloid leukemia (AML) patients limits the use of aggressive chemotherapy leading to poor overall survival. Alternative treatment strategies for AML are highly sought after. Our research has revealed vitamin C (ascorbate) to be a potential non-toxic therapeutic adjuvant for the treatment of AML. Ascorbate is an essential micronutrient in humans that, in addition to its role as a cellular antioxidant, participates as a direct cofactor of Ten-eleven (TET) enzymes. Mammalian TET proteins (TET1-3) are tumor suppressors of the hematopoietic lineage that catalyze the oxidation of 5-methylcytosine (5mC) leading to DNA demethylation and the reversal of gene silencing. TET2 loss-of-function mutations are frequently observed in AML patients and are associated with a worse overall prognosis. Importantly, TET2 mutations are almost always heterozygous, suggesting that enhancing residual TET2 activity (encoded by the remaining wild- type TET2 allele) could be a viable therapeutic strategy for the treatment of TET2-mutant AML. We have shown in cellular and animal models that ascorbate, in a TET-dependent manner, reprograms the AML epigenome by increasing DNA hydroxymethylation, leading to DNA demethylation, a block in aberrant self-renewal, increased differentiation, and slowing of leukemia progression. We hypothesize that ascorbate will be an effective therapeutic agent in the treatment of TET2 mutant AML by enhancing residual TET tumor suppressive function. There are currently no other therapeutic agents that target TET proteins for functional restoration. We propose to understand the mechanistic basis of how physiological or pharmacological doses of ascorbate influence TET activity, and whether uptake capacity through sodium-dependent vitamin C transporters or total residual TET activity influences ascorbate treatment efficacy (Aim1). AML progression in the context of TET2 mutation and diverse oncogenic drivers will be tested for sensitivity to ascorbate in combination with standard AML chemotherapy, and data already obtained from our loss of function genetic screens in AML cells will be used to design rational combinatorial treatment strategies that maximize the efficacy of ascorbate as a therapeutic adjuvant (Aim2). Finally, we will explore approaches to enhance the bioavailability of ascorbate as a TET2 cofactor using lipophilic ascorbyl analogs and genetic or pharmacological modulation of vitamin C transporters on AML cells (Aim3). The goal of this proposal is to understand the dose and AML context in which ascorbate treatment will be most efficacious, how to combine ascorbate with existing therapies to improve treatment outcome and identify novel approaches to enhance ascorbate bioavailability for increased TET-activating potential. We believe these studies will provide a strong foundation for clinical translation of ascorbate as a non- toxic adjuvant in combination therapies for the treatment of AML.

项目摘要 大多数急性髓性白血病（AML）患者的高龄限制了侵袭性化疗的使用。 化疗导致总体生存率低。AML的替代治疗策略备受追捧。 我们的研究表明，维生素C（抗坏血酸）是一种潜在的无毒治疗佐剂， AML的治疗。抗坏血酸盐是人体必需的微量营养素，除了作为细胞因子的作用外， 抗氧化剂，作为10 - 11（泰特）酶的直接辅因子参与。哺乳动物泰特蛋白（TET 1 -3） 是造血谱系的肿瘤抑制因子，催化5-甲基胞嘧啶（5 mC）的氧化 导致DNA去甲基化和基因沉默的逆转。TET 2功能缺失突变通常 在AML患者中观察到，并且与更差的总体预后相关。重要的是，TET 2突变是 几乎总是杂合的，这表明增强残余TET 2活性（由剩余的野生型编码）， TET 2型等位基因）可能是治疗TET 2突变型AML的可行治疗策略。我们已经表明 在细胞和动物模型中，抗坏血酸以TET依赖性方式通过以下方式重编程AML表观基因组： 增加DNA羟甲基化，导致DNA去甲基化，这是一种异常自我更新的阻滞， 分化和减缓白血病进展。我们假设抗坏血酸是一种有效的 本发明提供了通过增强残余泰特肿瘤抑制功能治疗TET 2突变型AML的治疗剂。 目前没有靶向泰特蛋白用于功能恢复的其他治疗剂。我们提出 了解生理或药理剂量的抗坏血酸如何影响泰特的机制基础 活性，以及是否通过钠依赖性维生素C转运蛋白或总残留泰特的摄取能力 活性影响抗坏血酸治疗功效（Aim 1）。TET 2突变背景下的AML进展和 将测试不同致癌驱动因子对抗坏血酸盐的敏感性， 化疗，以及我们已经从AML细胞功能丧失遗传筛查中获得的数据将用于 设计合理的组合治疗策略，最大限度地提高抗坏血酸作为治疗药物的功效 佐剂（Aim 2）。最后，我们将探索提高抗坏血酸作为TET 2的生物利用度的方法。 使用亲脂性抗坏血酸类似物的辅因子和维生素C转运蛋白的遗传或药理学调节 AML细胞（Aim 3）。本提案的目的是了解抗坏血酸的剂量和AML背景， 如何将抗坏血酸联合收割机与现有的治疗方法相结合，以改善治疗效果 结果并确定提高抗坏血酸生物利用度以增加TET激活的新方法 潜力我们相信这些研究将为抗坏血酸作为一种非抗坏血酸药物的临床应用提供坚实的基础。 在用于治疗AML的组合疗法中的毒性佐剂。