Assessment of Metabolites Among Asymptomatic Precursor and Malignant Monoclonal Gammopathies

项目摘要 多发性骨髓瘤（MM）是一种毁灭性的克隆性浆细胞（cPC）恶性肿瘤，导致超过13，000例多发性骨髓瘤。 美国每年死亡人数它总是在癌前病变，无症状的浆细胞疾病，如 意义不明的单克隆丙种球蛋白病（MGUS）或郁积型多发性骨髓瘤（SMM）。 尽管存在各种临床、基因组和基于成像的风险分层模型， 前体cPC疾病的分类及其进展为MM的风险仍然难以捉摸。根本 障碍仍然是现有的临床和实验室生物标志物无法区分 患者中存在癌前病变或恶性cPC。相比之下，最近在大规模- 基于光谱学的代谢组学为表征细胞内和细胞外代谢物提供了新的机会 这可以作为反映恶性cPC存在的新生物标志物。这是特别有希望的 由于已知癌前病变向恶性cPC进展的致癌驱动因子，如c-Myc， 对多种细胞内代谢途径的下游影响，导致细胞外代谢物改变 程度.可以利用这些所得代谢物谱来更准确地评估肿瘤进展的风险。 前体cPC疾病在未来的MM，并最终影响管理和治疗。因此， 一项研究计划将检验骨髓（BM）中选定代谢物的水平 血浆中c-Myc激活的恶性cPC的定性和定量存在反映了患者中c-Myc激活的恶性cPC的定性和定量存在 PC紊乱本研究建议将具体验证存在差异的水平， 选择MGUS和MM患者之间BM血浆中的代谢物（目的1）。它还将评估 cPC中c-Myc在这些选定代谢物的细胞外水平上的活化（目的2）。最后，它将评估 全身治疗如何消除恶性cPCs影响这些选择的BM血浆水平 MM中的代谢物（目的3）。这些研究将为我们提供一个机会， 与MM发病机制相关的代谢重新布线。这可以使我们更好地确定 从MGUS转变为症状性MM，以开发潜在的早期诊断或预防措施 战略布局团队成员的专业知识和资源，骨髓瘤孢子的可用性 生物库和NIH指定的综合代谢组学核心在马约诊所确保了生存能力， 执行拟议的实验。

PROJECT SUMMARY Multiple myeloma (MM) is a devastating clonal plasma cell (cPC) malignancy responsible for over 13,000 deaths in the US per year. It is always preceded by pre-malignant, asymptomatic plasma cell disorders such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). Despite the availability of various clinical, genomic, and imaging-based risk stratification models, accurate classification of precursor cPC disorders and their risk of progression to MM remains elusive. The fundamental roadblock remains in the inability of existing clinical and laboratory-based biomarkers to distinguish between the presence of premalignant or malignant cPCs in patients. In contrast, recent advances in mass- spectrometry based metabolomics offers new opportunities to characterize intra- and extracellular metabolites that could serve as novel biomarkers reflective of the presence of malignant cPCs. This is especially promising since oncogenic drivers of progression of premalignant to malignant cPCs, such as c-Myc, has known downstream effects on multiple intracellular metabolic pathways resulting in altered extracellular metabolite levels. These resultant metabolite profiles can be exploited to more accurately assess the risk of progression of precursor cPC disorders to MM in the future and ultimately affect management and treatment. Thus, this research proposal will test the hypothesis that the levels of select metabolites within the bone marrow (BM) plasma are reflective of the qualitative and quantitative presence of c-Myc-activated malignant cPCs in patients with PC disorders. This research proposal will specifically validate the presence of differences in the levels of select metabolites in the BM plasma between MGUS and MM patients (Aim 1). It will also evaluate the effect of c-Myc activation in cPCs on their extracellular levels of these select metabolites (Aim 2). Finally, it will evaluate how depleting the malignant cPCs with systemic therapy affects the BM plasma levels of these select metabolites in MM (Aim 3). These studies will provide an opportunity to advance our understanding of the metabolic rewiring associated with the pathogenesis of MM. This could allow us to better determine the transition from MGUS to symptomatic MM for the development of potential early diagnostic or preventative strategies. The expertise and resources of the members of the team, the availability of the Myeloma SPORE biobank and a NIH-designated comprehensive metabolomics core at the Mayo Clinic ensures the viability and execution of the proposed experiments.