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（由申请人提供）：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癌前阶段，称为意义未明的单克隆丙种球蛋白病 (MGUS)，或者是不太普遍、较晚期的阶段，称为冒烟型 MM (SMM)。 MGUS 和 SMM 患者表现出进展为 MM 的显着风险，估计每年的进展率分别为 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。由于目前确定的危险因素缺乏足够的准确性来证明无症状患者使用具有相当大毒性的药物开始治疗的合理性，我们的具体目标是确定准确的生物标志物来检测 PC 恶性转化的最早阶段，以便进展过程中的 MGUS 和 SMM 患者可以在严重的终末器官损伤发生之前就被识别出来。已经确定了许多有用的预后因素，然而，该领域仍然缺乏准确且敏感的生物标志物来识别尽管无症状但已开始进展的 MGUS 和 SMM 患者。尽管 MGUS 和 SMM PC 带有 MM 典型的遗传损伤，但令人惊讶的是，它们可以多年来保持显着的稳定，这表明存在目前未知的进一步扩张障碍。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常见主题包括代谢变化、肿瘤微环境 (ME) 重塑和细胞增殖增加，所有这些也在 MM 中被发现。在初步研究中，我们获得了令人兴奋的证据，表明跨膜 CD147 分子，也称为 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 进展的一种非常有前途的生物标志物，而且恶性 PC 需要其表达才能生长和存活，以及其以促进疾病进一步进展的方式修改 ME 的能力。提出了两个目标。目标 1 将评估 PC CD147 表达识别疾病进展的无症状 MGUS 和 SMM 患者的能力。目标 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源于将获得的机制见解以及 CD147 在进展为 MM 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，也将促进针对 CD147 的新型靶向疗法的开发。