CD147 Biological Function and Role as a Biomarker of MGUS to Myeloma Progression

CD147 的生物学功能和作为 MGUS 骨髓瘤进展生物标志物的作用

• 批准号: 8222093
• 负责人: Diane F Jelinek
• 金额: $ 17.15万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8222093
• 关键词: Adult; Affect; Age; Animal Model; Biological; Biological Markers; Biological Models; Biological Process; Bone Marrow; Cell Line; Cell Proliferation; Cells; Clinical; Coculture Techniques; Cyclophilin A; Data; Development; Diagnosis; Disease; Disease Outcome; Disease Progression; Early Diagnosis; Event; Exhibits; Extracellular Matrix; Fostering; Genetic; Goals; Growth; Hematologic Neoplasms; Human; Immunoglobulins; In Vitro; Individual; Lesion; Ligands; Malignant - descriptor; Malignant Neoplasms; Matrix Metalloproteinases; Measures; Messenger RNA; Metabolic; Modification; Molecular Abnormality; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mutation; Organ; Pathogenesis; Patients; Plasma Cells; Play; Positioning Attribute; Premalignant; Process; Production; Prognostic Factor; Risk; Risk Factors; Role; Serum; Staging; Stromal Cells; Testing; Time; Toxic effect; advanced disease; angiogenesis; extracellular; high risk; in vivo; insight; interest; novel; prognostic; therapeutic target; tool; tumor; tumor progression

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable and fatal clonal plasma cell (PC) malignancy. All MM cases are 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). MGUS and SMM patients exhibit significant risk of progression to MM, with rates estimated at 1% and 10% per year, respectively. Importantly, a diagnosis of MM depends on overt clinical manifestations of serious end-organ damage. Therefore, treatment is not initiated before evolving MGUS and SMM patients reach an advanced disease stage. Because currently identified risk factors lack sufficient accuracy to justify treatment initiation of asymptomatic patients using agents with considerable toxicities, our specific goal is to identify accurate biomarkers that detect the earliest stage of PC malignant transformation such that MGUS and SMM patients in the process of progressing can be identified prior to the onset of serious end-organ damage. A number of useful prognostic factors have been identified, however, the field still lacks an accurate and sensitive biomarker(s) that identifies MGUS and SMM patients who, in spite of being asymptomatic, have begun to progress. Although MGUS and SMM PCs harbor genetic lesions typical of MM, they can somewhat surprisingly remain remarkably stable for years suggesting the presence of a currently unknown barrier(s) to further expansion. Because these initial lesions are insufficient to cause symptomatic disease, the critical question that needs to be answered is what are the specific biological/genetic changes that occur to permit the abnormal PC clone to overcome this barrier(s) in patients who progress to MM? In this regard, it is notable that common themes observed during malignant progression include metabolic changes, remodeling of the tumor microenvironment (ME), and increased cell proliferation, all of which have also been identified in MM. In preliminary studies, we have obtained provocative evidence that the transmembrane CD147 molecule, also known as EMMPRIN (extracellular matrix metalloproteinase [MMP] inducer), may be playing an important biological role in MM PCs and that its expression may become induced during disease progression. Thus, we hypothesize that CD147 is not only an exceptionally promising biomarker of MGUS and SMM progression, but that malignant PCs require its expression for growth and survival as well as for its ability to modify the ME in a manner that fosters further disease progression. Two aims are proposed. Aim 1 will evaluate the ability of PC CD147 expression to identify asymptomatic MGUS and SMM patients with evolving disease. Aim 2 will elucidate the role of CD147 in MM cell proliferation and modification of the tumor ME. The overall impact of our study derives from the mechanistic insights that will be gained and the discovery of an important role for CD147 in progression to MM. Furthermore, demonstration that this molecule is required for disease progression and/or pathogenesis would also foster development of novel targeted therapies to CD147. PUBLIC HEALTH RELEVANCE: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to the typically fatal plasma cell (PC) cancer, multiple myeloma (MM). Currently, we lack accurate biomarkers able to detect patients in the process of progressing prior to serious end-organ damage. Our data suggest that the CD147 molecule is an exceptionally promising biomarker of MGUS and SMM progression and we hypothesize that it is essential for malignant PC proliferation and modification of the tumor microenvironment. Our overall goal is to identify MGUS and SMM patients with evolving disease and define therapeutic targets that might uniquely eliminate the evolving abnormal PCs.

描述（由申请方提供）：多发性骨髓瘤（MM）是一种无法治愈的致命性克隆性浆细胞（PC）恶性肿瘤。 所有MM病例之前都有一个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），或一个不太流行的，更先进的阶段，称为阴燃MM（SMM）。 MGUS和SMM患者表现出进展为MM的显著风险，估计发生率分别为每年1%和10%。 重要的是，MM的诊断取决于严重终末器官损伤的明显临床表现。 因此，在进展中的MGUS和SMM患者达到晚期疾病阶段之前不开始治疗。 由于目前确定的风险因素缺乏足够的准确性来证明使用具有相当大毒性的药物对无症状患者进行治疗的合理性，因此我们的具体目标是确定检测PC恶性转化的最早阶段的准确生物标志物，以便可以在严重终末器官损伤发生之前识别处于进展过程中的MGUS和SMM患者。 已经鉴定了许多有用的预后因素，然而，该领域仍然缺乏鉴定MGUS和SMM患者的准确和敏感的生物标志物，这些患者尽管无症状，但已经开始进展。 尽管MGUS和SMM PC具有MM典型的遗传病变，但它们可以令人惊讶地保持多年的显著稳定，这表明存在目前未知的进一步扩展的障碍。 由于这些初始病变不足以引起症状性疾病，因此需要回答的关键问题是，在进展为MM的患者中，发生了哪些特定的生物学/遗传学变化，以允许异常PC克隆克服这一障碍？ 在这方面，值得注意的是，在恶性进展期间观察到的共同主题包括代谢变化、肿瘤微环境（ME）重塑和细胞增殖增加，所有这些也在MM中被鉴定。（细胞外基质金属蛋白酶[MMP]诱导剂）可能在MM PC中发挥重要的生物学作用，并且其表达可能在疾病进展期间被诱导。 因此，我们假设CD 147不仅是MGUS和SMM进展的特别有前途的生物标志物，而且恶性PC需要其表达以促进进一步疾病进展的方式来生长和存活以及其修饰ME的能力。 提出了两个目标。目的1将评估PC CD 147表达识别无症状MGUS和SMM患者的能力。 目的2将阐明CD 147在MM细胞增殖和肿瘤ME修饰中的作用。我们研究的总体影响来自于将获得的机制见解以及CD 147在MM进展中的重要作用的发现。此外，证明这种分子是疾病进展和/或或发病机制也将促进对CD 147的新靶向疗法的开发。 公共卫生关系：意义不明的单克隆丙种球蛋白病（MGUS）和郁积型多发性骨髓瘤（SMM）是典型的致命性浆细胞（PC）癌多发性骨髓瘤（MM）的无症状前驱疾病。 目前，我们缺乏准确的生物标志物，能够在严重的终末器官损伤之前检测出处于进展过程中的患者。 我们的数据表明，CD 147分子是MGUS和SMM进展的一个非常有前途的生物标志物，我们假设它是恶性PC增殖和肿瘤微环境修饰所必需的。 我们的总体目标是确定MGUS和SMM患者与发展中的疾病，并确定治疗靶点，可能会独特地消除发展中的异常PC。