Metabolic Reprogramming: Essential Role and Early Marker of MGUS Progression

描述(申请人提供)：多发性骨髓瘤(MM)是一种毁灭性的、不可治愈的克隆性浆细胞(PC)恶性肿瘤，在此之前有一种非常普遍的无症状的癌前阶段，称为未确定意义的单克隆性伽马病(MGUS)或一种较不常见的、更高级的阶段，称为阴燃MM(SMM)。这两组患者都有显著增加的终身进展为多发性骨髓瘤的风险，然而，只有在有明显的严重终末器官损害的临床表现时，才能做出多发性骨髓瘤的诊断。因此，MGUS和SMM患者在出现症状之前不会接受治疗。尽管已经确定了一些有用的预后因素，但该领域仍然缺乏准确和敏感的生物标记物(S)来识别在出现症状之前就已经开始进展的MGUS和SMM患者。在这方面，人们已经知道癌细胞经历了一种独特的代谢适应，通过这种适应，葡萄糖摄取显著增加，以满足随着肿瘤进展而增加的细胞增殖速度所产生的对核苷酸、脂类和氨基酸的需求。这种被称为有氧糖酵解(AG)的代谢变化被认为是由线粒体缺陷、致癌信号、微环境缺氧和某些代谢酶的异常表达所促进的。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。癌细胞优先糖酵解代谢的几乎普遍的特征表明，这种改变提供了选择性的增殖优势，并可能是肿瘤进展中的一个必要步骤。在这一点上，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。尽管多发性骨髓瘤细胞具有FDG亲和力，但细胞代谢改变作为MGUS和SMM进展为多发性骨髓瘤的一个重要因素的作用仍未被研究。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途径的激活是导致遗传差异的MGUS和SMM向MM进展的共同的、统一的事件。在此，我们建议在PC水平上评估AG将提供一种新的、敏感和准确的手段来早期发现MGUS和SMM向MM的过渡。目的1确定MGUS、SMM和MM患者中异常PC的代谢表型，并确定导致这种代谢改变的关键AG基因。已识别的AG基因也将作为候选生物标记物，用于准确识别进展为MM但仍无症状的MGUS和SMM患者。目的2将确定这些关键的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械洞察力和新生物标记物的发现。此外，证明某些AG基因是疾病进展和/或发病所必需的，这也将促进新的靶向治疗的发展。 公共卫生相关性：多发性骨髓瘤(MM)是一种典型的致命性浆细胞(PC)癌，在此之前有两种无症状的前驱症状，即未确定意义的单克隆性伽马病(MGUS)和阴燃MM(SMM)。我们假设代谢重编程导致葡萄糖消耗显著增加，在疾病进展到MM过程中起着至关重要的作用。我们的目标是确定导致代谢重编程的特定基因变化，从而确定重要的治疗靶点和生物标记物，在MGUS和SMM患者演变为有症状的MM之前识别它们。

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. PUBLIC HEALTH RELEVANCE: Multiple myeloma (MM) is a typically fatal plasma cell (PC) cancer that is preceded by two asymptomatic precursor conditions, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). We hypothesize that metabolic reprogramming, which causes a significant increase in glucose consumption, plays an essential role in disease progression to MM. We aim to identify the specific genetic changes that cause metabolic reprogramming thereby identifying important therapeutic targets as well as biomarkers that would identify patients with MGUS and SMM before they evolve into symptomatic MM.