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.

项目摘要大多数急性髓样白血病（AML）患者的高龄限制了使用侵略性的化学疗法导致整体生存率差。高度追捧AML的替代治疗策略。我们的研究表明，维生素C（抗坏血酸）是潜在的无毒治疗辅助药 AML的处理。抗坏血酸是人类中必不可少的微量营养素，除了其作为细胞的作用外抗氧化剂，作为十个酶（TET）酶的直接辅助因子。哺乳动物TET蛋白（TET1-3）是造血谱系的肿瘤抑制因子，可催化5-甲基环肽的氧化（5MC）导致DNA脱甲基化和基因沉默的逆转。 TET2功能丧失突变经常是在AML患者中观察到，并且总体预后较差。重要的是，TET2突变是几乎总是杂合的，这表明增强了残留TET2活性（由剩余的野生编码 TET2等位基因类型）可能是治疗TET2突变AML的可行治疗策略。我们已经显示了在以TET依赖性方式抗坏血酸的细胞和动物模型中，通过增加DNA羟甲基，导致DNA脱甲基化，一个异常自我更新的块，增加了分化和白血病进展减慢。我们假设抗坏血酸是有效的通过增强残留的TET肿瘤抑制功能来治疗TET2突变体AML的治疗剂。目前，尚无其他治疗剂靶向TET蛋白用于功能恢复。我们建议了解生理或药理剂量如何影响TET的机械基础活性，以及通过依赖钠的维生素C转运蛋白的吸收能力还是总残留TET 活动会影响抗坏血酸治疗功效（AIM1）。在TET2突变和将测试各种致癌驱动因素，以便对抗坏血酸酯与标准AML结合使用敏感性化学疗法以及已经从AML细胞中功能遗传筛选丧失获得的数据将用于设计合理组合治疗策略，最大化抗坏血酸的疗效为治疗佐剂（AIM2）。最后，我们将探索方法以增强抗坏血酸的生物利用度为TET2 使用亲脂尾类似物以及维生素C转运蛋白的遗传或药理调节的辅助因子在AML细胞上（AIM3）。该提案的目的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增强抗坏血酸生物利用度以增加TET激活的新方法潜在的。我们认为，这些研究将为抗坏血酸作为非 - 用于治疗AML的组合疗法中的有毒佐剂。