Tumor Cell-Intrinsic/Extrinsic Mechanisms Underlying Myeloma Disease Progression

骨髓瘤疾病进展的肿瘤细胞内在/外在机制

基本信息

批准号：
9102046
负责人：
Diane F Jelinek
金额：
$ 36.37万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9102046
关键词：
Age Biological Biological Markers Biological Models Bone Diseases Bone Marrow Bone marrow biopsy Cancerous Cell Communication Cell Line Cell physiology Cells Cellular Stress Characteristics Chromosomal translocation Clinical Development Disease Disease Progression Etiology Extramedullary Frequencies Genetic Genomics Goals Health Heterogeneity Immune In Situ Intervention Kidney Failure Life Location Longitudinal Studies Lytic Malignant - descriptor Malignant Neoplasms Medical Modification Monoclonal gammopathy of uncertain significance Multiple Myeloma Mutation Nature Organ Outcome Patients Pattern Plasma Cells Premalignant Premalignant Cell Process Progressive Disease Recurrence Retrospective Studies Risk Role Shapes Staging Statistical Data Interpretation Stress Testing Toxic effect Trisomy Tumor-Derived density experience insight microvesicles migration mouse model neoplastic cell normal aging novel novel therapeutic intervention spatial relationship specific biomarkers tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is an incurable malignancy of clonal plasma cells (PC). The development of MM is typically preceded by asymptomatic precursor conditions termed monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Although both conditions are characterized by the accumulation of abnormal, but not yet cancerous, clonal PCs in the bone marrow (defined by <10% bone marrow PCs in MGUS vs >10% in SMM), many of these patients will never progress to MM and the frequency of their clonal BMPCs remains remarkably stable for years. However, all MGUS and SMM patients have a lifelong risk of progression to MM at a rate of ~1% and 10% per year, respectively. Because of the low transformation rate into malignancy and the toxicity of current treatments, no medical intervention is begun for MGUS or low risk SMM patients until after irreversible end-organ damage (e.g., lytic bone disease, and renal insufficiency) has occurred. It is clearly desirable to begin treatment before patients become symptomatic, but specific biomarkers that accurately predict which patients will progress to malignancy and also yield insight into the mechanisms responsible for transformation to MM do not currently exist. Given that specific trisomies and chromosomal translocations characteristic of MM PCs are already present in the clonal PCs in MGUS and SMM patients, these changes alone are not responsible for malignancy. Longitudinal studies over the past decade that have focused on identifying specific MM PC-intrinsic genomic changes that are characteristic of malignant transformation have been only marginally successful and although recurrent mutations have been identified, there is significant patient to patient heterogeneity and many unanswered questions concerning disease progression remain. The primary focus of this proposal is on changes in the BM microenvironment (ME) and the relationship between innate and adaptive immune cells in close proximity to abnormal BMPCs during disease progression from MGUS/SMM to malignant MM. The BMPC immune contexture (in situ immune cell nature, density, functional orientation, and spatial relationships) and its potential role in MGUS/SMM progression to MM have not been previously studied. Our specific hypothesis is that the BM ME actively suppresses disease progression in MGUS and SMM patients and that focal changes in the ME relieve the suppression and allow abnormal PCs in these modified niches to expand. These changes may be due to either deviations in the composition or function of the cells within the PC niche as a result of age, or may represent migration of the premalignant cells into a niche which is favorable to disease progression. We also hypothesize that changes to the BM ME may actually be driven by the abnormal PCs themselves and their release of microvesicles (MVs) that regionally expand the BMPC niche and facilitate systemic spread. This proposal will therefore focus on PC and MV-driven alterations of immune cells in the BM ME during MM progression, the functional consequences of these changes, and correlation with clinical outcome.

描述（由申请人提供）：多发性骨髓瘤 (MM) 是一种无法治愈的克隆性浆细胞 (PC) 恶性肿瘤，在发生 MM 之前通常会出现被称为意义未明的单克隆伽马病 (MGUS) 和冒烟性骨髓瘤 (SMM) 的无症状先兆病症。尽管这两种情况的特征都是骨髓中异常但尚未癌变的克隆 PC 的积累（定义为MGUS 中骨髓 PC<10%，SMM 中>10%），其中许多患者永远不会进展为 MM，并且其克隆 BMPC 的频率多年来保持异常稳定。然而，所有 MGUS 和 SMM 患者都存在终生风险。每年进展为 MM 的速度分别约为 1% 和 10% 由于恶性转化率较低且当前治疗方法具有毒性，因此未对 MGUS 或低风险 SMM 患者开始医疗干预。直到发生不可逆的终末器官损伤（例如溶骨病和肾功能不全）后，显然需要在患者出现症状之前开始治疗，但可以准确预测哪些患者将进展为恶性肿瘤并深入了解特定的生物标志物。鉴于 MM PC 的特定三体性和染色体易位特征已存在于 MGUS 和 SMM 患者的克隆 PC 中，目前尚不存在导致 MM 转化的机制。过去十年的纵向研究专注于识别恶性转化特征的特定 MM PC 内在基因组变化，但仅取得了一定程度的成功，尽管已经发现了复发性突变，但仍有大量患者需要等待。患者异质性和有关疾病进展的许多未解答的问题仍然存在。该提案的主要重点是 BM 微环境 (ME) 的变化以及疾病期间与异常 BMPC 密切相关的先天免疫细胞和适应性免疫细胞之间的关系。 BMPC 免疫环境（原位免疫细胞性质、密度、功能方向和空间关系）及其在 MGUS/SMM 进展为 MM 中的潜在作用尚未被研究过。 BM ME 积极抑制 MGUS 和 SMM 患者的疾病进展，ME 的局灶性变化缓解了抑制并允许这些修饰的微环境中的异常 PC 扩展，这些变化可能是由于成分或功能的偏差。我们还发现，BM ME 的变化实际上可能是由异常 PC 本身驱动的。它们释放的微泡（MV）可在区域范围内扩大 BMPC 生态位并促进系统性扩散，因此本提案将重点关注 MM 进展过程中 BM ME 中 PC 和 MV 驱动的免疫细胞变化、这些变化的功能后果以及相关性。和临床结果。