Enhancing TET activity for the treatment of hematological malignancy

增强 TET 活性治疗血液恶性肿瘤

基本信息

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
项目类别：
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

项目摘要

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.

项目概要大多数急性髓系白血病 (AML) 患者的高龄限制了积极治疗的使用化疗导致总体生存率较差。 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。抗坏血酸是人类必需的微量营养素，除了作为细胞的作用外，抗氧化剂，作为 10-11 (TET) 酶的直接辅因子参与。哺乳动物 TET 蛋白 (TET1-3) 是造血谱系的肿瘤抑制因子，催化 5-甲基胞嘧啶 (5mC) 的氧化导致DNA去甲基化和基因沉默的逆转。 TET2 功能丧失突变经常发生在 AML 患者中观察到，并且与较差的总体预后相关。重要的是，TET2 突变是几乎总是杂合的，这表明增强残留的 TET2 活性（由剩余的野生型编码） TET2 型等位基因）可能是治疗 TET2 突变 AML 的可行治疗策略。我们已经展示了在细胞和动物模型中，抗坏血酸以 TET 依赖性方式重新编程 AML 表观基因组增加 DNA 羟甲基化，导致 DNA 去甲基化，阻止异常的自我更新，增加分化和减缓白血病进展。我们假设抗坏血酸将是一种有效的通过增强残余 TET 肿瘤抑制功能来治疗 TET2 突变型 AML 的治疗剂。目前没有其他治疗药物可以靶向 TET 蛋白来恢复功能。我们建议了解抗坏血酸的生理或药理学剂量如何影响 TET 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 TET 摄取能力活性影响抗坏血酸治疗效果（目标 1）。 TET2 突变背景下的 AML 进展和将结合标准 AML 测试不同致癌驱动因素对抗坏血酸的敏感性化疗，以及我们从 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，最大限度地发挥抗坏血酸作为治疗药物的功效佐剂（目标2）。最后，我们将探索提高抗坏血酸作为 TET2 的生物利用度的方法使用亲脂性抗坏血酸类似物和维生素 C 转运蛋白的遗传或药理学调节的辅助因子 AML 细胞（目标 3）。该提案的目标是了解抗坏血酸的剂量和 AML 背景治疗将是最有效的，如何将抗坏血酸与现有疗法相结合以改善治疗结果并确定提高抗坏血酸生物利用度以增加 TET 激活的新方法潜在的。我们相信这些研究将为抗坏血酸作为非抗坏血酸的临床转化提供坚实的基础。治疗 AML 联合疗法中的毒性佐剂。