Defining and targeting asparaginase resistance mechanisms in high-risk acute leukemias

定义和针对高危急性白血病的天冬酰胺酶耐药机制

• 批准号: 10415133
• 负责人: Alejandro Gutierrez
• 金额: $ 43.37万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415133
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Amino Acids; Anabolism; Asparagine; B-Cell Acute Lymphoblastic Leukemia; Biology; Carcinoma; Cell Cycle Arrest; Cell Death; Clinical; Colon Carcinoma; Cytoplasmic Inclusion; Data; Disease; Drug Sensitization; Drug resistance; Enzymes; Generations; Genetic Screening; Hematopoietic stem cells; Human; Knowledge; Leukemic Cell; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Mutation; Myeloid Leukemia; N-terminal; Non-Essential Amino Acid; Normal Cell; Oncogenic; Pathway interactions; Phase; Phenocopy; Phosphotransferases; Process; Prognosis; Protein Isoforms; Proteins; Refractory; Regulation; Resistance; Resistance development; Role; Signal Transduction; Source; Starvation; Testing; Therapeutic; Therapeutic Index; Toxic effect; Translating; Ubiquitination; WNT Signaling Pathway; antileukemic agent; asparaginase; base; beta catenin; cancer therapy; curative treatments; experimental study; genome-wide; high risk; improved; in vivo; inhibitor; innovation; insight; interest; leukemia; leukemia relapse; logarithm; paralogous gene; patient derived xenograft model; prospective; protein degradation; resistance mechanism; response; therapeutically effective; treatment response

ABSTRACT Asparaginase, an antileukemic enzyme that depletes the nonessential amino acid asparagine, is a core component of front-line therapy for acute lymphoblastic leukemias. However, the development of resistance to asparaginase-based therapy is a common problem with a poor prognosis, and the biology underlying asparaginase response and resistance is not well understood. Using a genome-wide genetic screen, we recently found that Wnt pathway activation profoundly sensitizes drug-resistant leukemias to asparaginase. This effect occurs in distinct treatment-resistant subtypes of acute leukemia, including T-ALL, hypodiploid B-ALL, and acute myeloid leukemia, but not in normal hematopoietic progenitors. Asparaginase sensitization is independent of the canonical β-catenin branch of Wnt signaling. Instead, this effect is mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), an understudied branch of Wnt signaling that inhibits GSK3-dependent protein ubiquitination and proteasomal degradation. Inhibiting the alpha isoform of GSK3 is sufficient to phenocopy this effect. In vivo, the combination of GSK3α-selective inhibition and asparaginase has profound therapeutic activity against patient-derived xenografts that are completely resistant to monotherapy with either agent. Thus, asparaginase-resistant leukemias survive treatment with this enzyme by relying on protein degradation, a catabolic source of amino acids, to replenish the pool of intracellular asparagine. This adaptive response is blocked by Wnt pathway activation, or by selective inhibition of GSK3α. However, the molecular determinants of response and resistance to the combination of GSK3α inhibition and asparaginase are unknown. These knowledge gaps are major obstacles to the rational application of this potent therapeutic combination for maximal clinical benefit, which will be addressed by investigating the following Specific Aims: 1) Define the molecular basis for the therapeutic index of GSK3α inhibition and asparaginase, and 2) Investigate why asparaginase resistance is solely dependent on GSK3α, when its closely related paralog GSK3β is redundant for regulation of canonical Wnt/β-catenin signaling. Successful completion of this proposal is expected to reveal major insights into the cellular response to amino acid starvation and its interaction with Wnt signaling. These processes are fundamental to metazoan biology, yet their molecular regulation and therapeutic exploitation remain poorly understood. We are uniquely poised to translate these advances into highly innovative and effective therapeutic strategies to maximize the therapeutic index of asparaginase in cancer therapy.

抽象的 天冬酰胺酶，一种耗尽非必需氨基酸天冬酰胺的抗核酶酶，是核心 急性淋巴细胞白血病的前线治疗的成分。但是，发展对 基于天冬酰胺酶的治疗是预后不良的常见问题，而生物学的基础是 天冬酰胺酶的反应和抗性尚不清楚。使用全基因组遗传筛选，我们最近 发现Wnt途径激活深刻地感知了耐药性白血病与天冬酰胺酶。这个效果 发生在急性白血病的不同治疗抗性亚型中，包括T-ALL，下型b-all和急性 髓样白血病，但不在正常的造血祖细胞中。天冬酰胺酶敏感性独立于 Wnt信号传导的规范β-catenin分支。相反，这种效应是由Wnt依赖性稳定介导的 蛋白质（Wnt/stop），这是Wnt信号的理解分支，抑制GSK3依赖性蛋白 泛素化和蛋白酶体降解。抑制GSK3的α同工型足以进行苯术 影响。在体内，GSK3α选择性抑制和白黄大酶的结合具有深刻的治疗活性 针对患者衍生的异种移植物，这些异种移植物完全抵抗任何两种药物的单一疗法。那， 天冬酰胺酶耐白血病的生存治疗通过这种酶来依靠蛋白质降解，A 氨基酸的分解代谢来源，以复制细胞内天冬酰胺的池。这种适应性反应是 被Wnt途径激活阻止，或通过选择性抑制GSK3α。但是，分子决定剂 对GSK3α抑制和天冬酰胺酶组合的反应和抗性是未知的。这些 知识差距是这种潜在疗法组合合理应用合理应用的主要障碍 临床益处将通过研究以下特定目的来解决：1）定义分子 GSK3α抑制和天冬氨酸酶的治疗指数的基础，以及2）研究为什么天冬酰胺酶 当其紧密相关的旁系同源物GSK3β冗余以调节时，抗性仅取决于GSK3α 典型的Wnt/β-catenin信号传导。预计该提案的成功完成将揭示主要见解 进入对氨基酸饥饿的细胞反应及其与Wnt信号的相互作用。这些过程是 基于后生生物学的基础，但它们的分子调节和热剥削仍然很差 理解齿。我们被毒死了，可以将这些进步转化为高度创新和有效的疗法 在癌症治疗中最大化天冬酰胺酶的治疗指数的策略。