Molecular Determinants of Methotrexate in Acute Lymphoblastic Leukemia

甲氨蝶呤治疗急性淋巴细胞白血病的分子决定因素

基本信息

批准号：
7413378
负责人：
JULIO C BARREDO
金额：
$ 29.74万
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：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7413378
关键词：
ABCC1 gene Accounting Acute Acute Lymphocytic Leukemia Address Affect Biochemical Biological Assay Blast Cell Cell Cycle Regulation Cell Extracts Cell Line Cell Lineage Cell membrane Cell model Cells Characteristics Child Childhood Acute Lymphocytic Leukemia Chimeric Proteins Chromosomal translocation Chromosome abnormality Chromosomes Clinical Clinical Trials Design Complementary DNA Conduct Clinical Trials DHFR gene Data Diagnosis Dihydrofolate Reductase Disease Disease-Free Survival Dose Down-Regulation Drug resistance Enrollment Enzymes Exhibits Figs - dietary Folate Folic Acid Antagonists Future Gene Expression Gene Frequency Gene Proteins Genes Genetic Transcription Glioma Hematopoietic Heterogeneity Human In Vitro Individual Induced Mutation Investigation Knowledge Laboratories Lead Ligase Link Lymphoblastic Leukemia Mediating Messenger RNA Metabolic Metabolism Methotrexate Modeling Molecular Molecular Abnormality Molecular Profiling Molecular Target Mutagenesis Mutation Nuclear Nucleotides Numbers Other Therapy Outcome P-Glycoproteins Pathway interactions Patients Pattern Pharmaceutical Preparations Pharmacogenetics Phenotype Physiological Pilot Projects Plasmids Point Mutation Predisposition Prevalence Process Prodrugs Proteins Range Rate Relapse Reporter Genes Reporting Research Research Project Grants Research Proposals Resistance Risk Risk Assessment Role SLC19A1 gene Sampling Schedule Serum Single Nucleotide Polymorphism Specimen Time Toxic effect Transcript Treatment outcome antileukemic agent base chemotherapy clinical phenotype clinically relevant cytotoxicity design drug metabolism gamma-Glutamyl Hydrolase gene therapy improved in vivo lymphoblast methotrexate polyglutamate novel polyglutamate polyglutamates progesterone 11-hemisuccinate-(2-iodohistamine)protein expression resistance mechanism response tumor

项目摘要

DESCRIPTION (provided by applicant): This research project aims to increase our understanding of the mechanisms of action and resistance to methotrexate (MTX), a universal component of therapies for children with acute lymphoblastic leukemia (ALL). The long-term objectives are to incorporate this knowledge in the design of ALL trials based on novel molecular targets and to improve event-free survival (EFS) for patients with resistant phenotypes. Even though the antifolate MTX is widely used in ALL therapies, important unanswered questions remain with respect to molecular determinants of drug resistance, heterogeneity of clinical response, optimal dose(s) and schedule(s). It has been demonstrated that lymphoblast accumulation of MTX polyglutamates (MTX-PGs) correlates with clinical outcome. Metabolism to MTX-PGs depends on serum MTX concentration, transport across the cell membrane, and more important the cell lineage-specific expression of Folyl-gamma-polyglutamate Synthetase (FPGS). Non-random translocations that characterize ALL clones are important predictors of clinical outcome and characterize ALL subtypes that exhibit significant heterogeneity of FPGS expression. Due to their effects on gene transcription and cell cycle control, non-random translocations may alter drug metabolism and resistance. We hypothesize that molecular mechanisms associated with non-random translocations lead to differences in metabolism to MTX-PGs by altering lymphoblast FPGS expression. We propose these translocations represent molecular "pathways" present in leukemic clones that result in the heterogeneity of FPGS expression, patterns of MTX metabolism, and clinical response to MTX seen in childhood ALL subtypes. In addition, single nucleotide polymorphisms (SNPs) of FPGS have been recently identified in an ethnically diverse panel of individuals. We propose these SNPs also contribute to the heterogeneity of PFGS expression in ALL, and their prevalence and physiologic impact will be investigated. In addition, drug-induced mutations leading to in vitro resistance to anti-folates have been described. Consequently, we also hypothesize that drug-induced mutations of FPGS can be detected at the time of relapse from ALL and may represent a novel mechanism of resistance after relapse. More important, because these genetic abnormalities are not present in normal hematopoietic cells, they offer selective targets for gene therapy or other molecular approaches in ALL.

描述（由申请人提供）：该研究项目旨在提高我们对甲氨蝶呤（MTX）的作用机理的理解，这是针对患有急性淋巴细胞白血病（ALL）儿童疗法的普遍成分。长期目标是将这些知识纳入基于新的分子靶标的所有试验的设计中，并为具有抗性表型的患者改善无事件生存（EFS）。即使抗叶酸MTX在所有疗法中广泛使用，但在耐药性的分子决定因素，临床反应的异质性，最佳剂量，最佳剂量（S）和时间表方面仍然存在重要的未解决问题。已经证明，MTX聚谷氨酸（MTX-PGS）的淋巴细胞积累与临床结果相关。对MTX-PG的代谢取决于血清MTX浓度，跨细胞膜的转运以及更重要的是Folyl-Gamma--羟氨核酸谷氨酸合成酶（FPGS）的细胞谱系特异性表达。表征所有克隆的非随机易位是临床结果的重要预测指标，并且表征所有表现出明显异质性表达异质性的亚型。由于它们对基因转录和细胞周期控制的影响，非随机易位可能会改变药物代谢和抗性。我们假设与非随机易位相关的分子机制通过改变淋巴细胞FPGS表达而导致代谢与MTX-PG的差异。我们提出这些易位代表了白血病克隆中存在的分子“途径”，从而导致FPGS表达的异质性，MTX代谢模式以及对儿童期在所有亚型中看到的MTX的临床反应。此外，最近在一个种族多样化的个体小组中发现了FPG的单核苷酸多态性（SNP）。我们提出这些SNP还有助于所有人表达PFG的异质性，并将研究它们的患病率和生理影响。此外，已经描述了导致对抗脉络膜体外耐药性的药物诱导的突变。因此，我们还假设在从所有人复发时可以检测到药物诱导的FPG突变，并且可能代表了复发后的一种新型抗性机制。更重要的是，由于正常造血细胞中这些遗传异常不存在，因此它们为基因疗法或其他分子方法提供了选择性靶标。