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

描述（申请人提供）：多发性骨髓瘤（MM）是一种无法治愈且致命的克隆浆细胞（PC）恶性肿瘤。所有MM病例之前都有一个非常普遍的无症状的癌前阶段，称为未确定意义的单克隆伽玛病（MGUS），或一个不太普遍，更晚期的阶段，称为阴燃MM （SMM）。MGUS和SMM患者表现出显著的进展为MM的风险，估计分别为每年1%和10%。重要的是，MM的诊断依赖于严重终末器官损伤的明显临床表现。因此，在发展中的MGUS和SMM患者达到疾病晚期之前，不开始治疗。由于目前确定的危险因素缺乏足够的准确性，不足以证明无症状患者使用具有相当毒性的药物进行治疗是合理的，因此我们的具体目标是确定准确的生物标志物，以检测PC恶性转化的早期阶段，以便在进展过程中的MGUS和SMM患者可以在严重的终末器官损伤发生之前被识别出来。许多有用的预后因素已经被确定，然而，该领域仍然缺乏一种准确和敏感的生物标志物来识别MGUS和SMM患者，尽管无症状，但已经开始进展。尽管MGUS和SMM PCs具有典型的MM遗传病变，但它们可以在数年内保持相当稳定，这表明存在目前未知的进一步扩展障碍。由于这些初始病变不足以引起症状性疾病，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/遗传变化，使异常PC克隆能够克服这一障碍？在这方面，值得注意的是，在恶性进展过程中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，所有这些都在MM中被发现。在初步研究中，我们已经获得了令人兴奋的证据，证明跨膜CD147分子，也被称为EMMPRIN（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，并且在疾病进展过程中其表达可能被诱导。因此，我们假设CD147不仅是MGUS和SMM进展的一个非常有希望的生物标志物，而且恶性pc的生长和存活需要它的表达，以及它以一种促进疾病进一步进展的方式修饰ME的能力。提出了两个目标。目的1将评估PC CD147表达对无症状MGUS和病情发展的SMM患者的识别能力。目的2将阐明CD147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和CD147在MM进展中的重要作用的发现。此外，证明该分子是疾病进展和/或发病机制所必需的，也将促进CD147的新型靶向治疗的发展。

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.