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Metabolic Reprogramming: Essential Role and Early Marker of MGUS Progression

代谢重编程：MGUS 进展的重要作用和早期标志

基本信息

批准号：
8516477
负责人：
Diane F Jelinek
金额：
$ 19.5万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516477
关键词：
2-Fluoro-2-deoxyglucose Amino Acids Animal Model Avidity Biological Biological Markers Biological Models Bone Marrow Cell Line Cell Proliferation Cells Cellular Stress Cessation of life Characteristics Clinical Clinical Management Clonal Expansion Consumption Data Defect Deoxyglucose Development Diagnosis Disease Disease Progression Early Diagnosis Enzymes Event Exhibits Fostering Gene Mutation Genes Genetic Glucose Glucose Transporter Glycolysis Pathway Heavy-Chain Immunoglobulins Human Hypoxia Image Immunoglobulins KRAS2 gene Lactate Dehydrogenase Lesion Life Lipids Malignant - descriptor Malignant Neoplasms Membrane Potentials Metabolic Metabolism Mitochondria Monoclonal gammopathy of uncertain significance Multiple Myeloma Mutation Nucleotides Oncogenic Organ Oxygen Pathogenesis Pathway interactions Patients Phenotype Plasma Cells Play Positron-Emission Tomography Precancerous Conditions Premalignant Process Production Prognostic Factor Proto-Oncogene Proteins c-akt Pyruvate Kinase Recurrence Risk Role S-Phase Fraction Sampling Serum Signal Transduction Staging Symptoms Trisomy aerobic glycolysis base cancer cell daughter cell glucose uptake in vivo insight knock-down meetings mitochondrial membrane neoplastic cell novel overexpression therapeutic target tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is a devastating and incurable clonal plasma cell (PC) malignancy that is preceded by a highly prevalent asymptomatic premalignant stage termed monoclonal gammopathy of undetermined significance (MGUS) or a less prevalent, more advanced stage called smoldering MM (SMM). Both groups of patients have a significantly increased, life-long risk of progression to MM, however, a diagnosis of MM is not made until there are overt clinical manifestations of serious end-organ damage. As a result, MGUS and SMM patients with evolving disease do not receive treatment until they become symptomatic. Although a number of useful prognostic factors have been identified, the field still lacks an accurate and sensitive biomarker(s) that identifies MGUS and SMM patients who have begun to progress before displaying symptoms. In this regard, it has been known for over 75 years that cancer cells undergo a distinct metabolic adaptation by which glucose uptake is considerably enhanced to meet the augmented cellular demand for nucleotides, lipids, and amino acids created by increased rates of cellular proliferation accompanying tumor progression. This metabolic alteration, termed aerobic glycolysis (AG), is known to be promoted by mitochondrial defects, oncogenic signals, microenvironmental hypoxia, and abnormal expression of certain metabolic enzymes. AG also underlies the clinical utility of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the management of various tumors. The nearly universal characteristic of preferential glycolytic metabolism by cancer cells suggests this alteration provides a selective proliferative advantage and may potentially be a requisite step in tumor progression. In this regard, MM cells are known to display increased glucose uptake based on positive FDG-PET scans in these patients. Despite the FDG avidity of MM cells, the role of altered cellular metabolism as an essential factor in MGUS and SMM progression to MM remains uninvestigated. On this basis, as well as our preliminary data, we hypothesize that MGUS and SMM PC metabolic reprogramming resulting in activation of the AG pathway is the common, unifying event underlying genetically diverse MGUS and SMM progression to MM. Here, we propose that assessment of AG at the PC level will provide a novel, sensitive, and accurate means of early detection of MGUS and SMM transition to MM. Two specific aims are proposed. Aim 1 will determine the metabolic phenotype of abnormal PCs in MGUS, SMM, and MM patients, and identify key AG genes underlying this metabolic alteration. The identified AG genes will also serve as candidate biomarkers for accurately identifying MGUS and SMM patients who are progressing to MM but are still asymptomatic. Aim 2 will define the biological role of these key AG genes in MM cell proliferation. The overall impact of our study derives from the mechanistic insights that will be gained and the discovery of novel biomarkers. Furthermore, demonstration that certain AG genes are required for disease progression and/or pathogenesis would also foster development of novel targeted therapies.

描述（由申请方提供）：多发性骨髓瘤（MM）是一种毁灭性和不可治愈的克隆性浆细胞（PC）恶性肿瘤，在此之前存在高度流行的无症状癌前阶段（称为意义不明的单克隆丙种球蛋白病（MGUS））或不太流行的更晚期阶段（称为阴燃型MM（SMM））。两组患者进展为MM的终生风险均显著增加，然而，直到出现严重终末器官损伤的明显临床表现时才诊断为MM。因此，具有进展性疾病的MGUS和SMM患者直到出现症状才接受治疗。虽然已经确定了许多有用的预后因素，但该领域仍然缺乏准确和敏感的生物标志物，用于识别在显示症状之前已经开始进展的MGUS和SMM患者。在这方面，75年来已经知道癌细胞经历独特的代谢适应，通过这种代谢适应，葡萄糖摄取显著增强，以满足伴随肿瘤进展的细胞增殖速率增加所产生的对核苷酸、脂质和氨基酸的增加的细胞需求。这种代谢改变，称为有氧糖酵解（AG），已知是由线粒体缺陷，致癌信号，微环境缺氧和某些代谢酶的异常表达促进的。AG也是18F-2-氟-2-脱氧-D-葡萄糖正电子发射断层扫描（FDG-PET）在各种肿瘤治疗中的临床应用的基础。癌细胞优先糖酵解代谢的几乎普遍特征表明，这种改变提供了选择性增殖优势，可能是肿瘤进展的必要步骤。在这方面，已知MM细胞在这些患者中基于阳性FDG-PET扫描显示葡萄糖摄取增加。尽管MM细胞的FDG亲合力，但改变的细胞代谢作为MGUS和SMM进展为MM的重要因素的作用仍未得到研究。在此基础上，以及我们的初步数据，我们假设MGUS和SMM PC代谢重编程导致AG通路的激活是遗传多样性MGUS和SMM进展为MM的常见统一事件。以及早期发现MGUS和SMM向MM过渡的准确手段。目的1将确定MGUS，SMM和MM患者异常PC的代谢表型，并确定导致这种代谢改变的关键AG基因。鉴定的AG基因也将作为候选生物标志物，用于准确鉴定进展为MM但仍无症状的MGUS和SMM患者。目的2将明确这些关键AG基因在MM细胞增殖中的生物学作用。我们研究的总体影响来自于将获得的机制见解和新生物标志物的发现。此外，证明某些AG基因是疾病进展和/或发病机制所需的也将促进新的靶向疗法的开发。