Assessment of Metabolites Among Asymptomatic Precursor and Malignant Monoclonal Gammopathies

项目总结 多发性骨髓瘤(MM)是一种破坏性的克隆性浆细胞(CPC)恶性肿瘤，导致超过13,000人死亡 美国每年的死亡人数。它总是先于癌前的，无症状的浆细胞疾病，如 未确定意义的单克隆性伽马病(MGUS)或阴燃多发性骨髓瘤(SMM)。 尽管有各种基于临床、基因组和成像的风险分层模型，但准确的 前体CPC疾病的分类及其进展为多发性骨髓瘤的风险仍然难以捉摸。最基本的 障碍仍然是现有的临床和实验室生物标记物无法区分 患者中存在癌前病变或恶性病变。相比之下，质量方面的最新进展- 基于光谱学的代谢组学为表征细胞内外代谢物提供了新的机会 这可以作为反映恶性CC存在的新的生物标志物。这是特别有希望的 由于癌前病变向恶性病变进展的致癌驱动因素，如c-Myc，已知 下游对多条细胞内代谢途径的影响导致细胞外代谢产物的改变 级别。这些代谢物图谱可以被用来更准确地评估糖尿病进展的风险。 前驱CPC障碍对MM的未来并最终影响管理和治疗。因此，这一点 研究提案将检验这样一种假设，即骨髓(BM)中精选代谢物的水平 血浆反映c-Myc激活的恶性CPC在患者体内的定性和定量存在 患有个人电脑障碍。这项研究建议将具体验证在以下水平上存在的差异 在MGUS和MM患者之间选择骨髓血浆中的代谢物(目标1)。它还将评估以下方面的效果 C-Myc在CPC中的激活对其细胞外这些选定代谢物的水平(目标2)。最后，它将评估 用系统治疗耗尽恶性CPC对这些精选患者的BM血浆水平有何影响 MM中的代谢物(目标3)。这些研究将提供一个机会，加深我们对 代谢重排与MM的发病机制有关，这可以让我们更好地确定 从MGUS过渡到症状性多发性骨髓瘤以发展潜在的早期诊断或预防性 战略。团队成员的专业知识和资源，骨髓瘤孢子的可用性 Biobank和NIH指定的梅奥诊所的综合代谢组学核心确保了生存能力和 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.