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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

基本信息

批准号：
8434847
负责人：
Diane F Jelinek
金额：
$ 19.35万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
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/8434847
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 microenvironment tumor progression

项目摘要

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.

描述(申请人提供)：多发性骨髓瘤(MM)是一种无法治愈和致命的克隆性浆细胞(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性伽马病(MGUS)或较不常见的更晚期的阴燃MM(SMM)。MGUS和SMM患者表现出显著的进展到MM的风险，估计每年的发生率分别为1%和10%。重要的是，多发性骨髓瘤的诊断依赖于严重的终末器官损害的明显临床表现。因此，在MGUS和SMM患者发展到疾病晚期之前，不会开始治疗。由于目前识别的危险因素缺乏足够的准确性来证明使用具有相当毒性的药物的无症状患者开始治疗是合理的，我们的具体目标是识别准确的生物标记物，以检测PC恶变的最早阶段，以便在严重的终末器官损害发生之前识别进展过程中的MGUS和SMM患者。一些有用的预后因素已经确定，然而，该领域仍然缺乏准确和敏感的生物标记物(S)来识别MGUS和SMM患者，尽管他们没有症状，但已经开始进步。尽管MGUS和SMM PC存在典型的MM基因损伤，但令人惊讶的是，它们可以在多年中保持显著稳定，这表明存在目前未知的障碍(S)，无法进一步扩展。由于这些最初的损害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/基因变化，以允许异常的PC克隆克服这一障碍(S)？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，我们获得了具有挑衅性的证据，表明跨膜CD147分子，也被称为EMMPRIN(细胞外基质金属蛋白酶[MMP]诱导物)，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过程中被诱导。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记物，而且恶性PC需要它的表达来生长和生存，以及它以促进进一步疾病进展的方式改变ME的能力。提出了两个目标。目的1评价PC CD147表达对无症状MGUS和SMM患者病情演变的诊断价值。目的2阐明CD147在多发性骨髓瘤细胞增殖和肿瘤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洞察力和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/或发病所必需的，也将促进针对CD147的新型靶向治疗的开发。