Cancer Stem Cell Targeting in Multiple Myeloma

多发性骨髓瘤中的癌症干细胞靶向

• 批准号: 7588870
• 负责人: WILLIAM H MATSUI
• 金额: $ 27.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588870
• 关键词: Acute Myelocytic Leukemia; Biological; Cells; Clinical; Clinical Treatment; Clonal Expansion; Data; Development; Disease; Disease Progression; Disease remission; Drug resistance; Erinaceidae; Failure; Follicular Lymphoma; Frequencies; Growth; Hematologic Neoplasms; Human; In Vitro; Lead; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mature B-Lymphocyte; Memory B-Lymphocyte; Multiple Myeloma; Neoplastic Plasma Cell; Newly Diagnosed; Outcome; Pathway interactions; Patients; Pattern; Plasma Cells; Population; Production; Prognostic Factor; Property; Recurrent disease; Regulation; Relapse; Resistance; Role; Signal Pathway; Specimen; Stem cells; base; cancer stem cell; cell type; clinically relevant; clinically significant; drug sensitivity; in vivo; neoplastic cell; notch protein; novel; oncology; progenitor; response; self-renewal; smoothened signaling pathway; stem; stem cell fate; therapeutic target; tumor

DESCRIPTION (provided by applicant): Accumulating evidence suggest that many human cancers consist of functionally heterogeneous cells organized in a hierarchical manner with less mature cancer stem cells (CSC) giving rise to differentiated tumor cells. The distinction between these cell types has important implications for the development of effective anti- cancer strategies as mature tumor cells that form the majority of cells and phenotypically characterize the disease lack long-term replicative potential. In contrast, rare CSC appear to arise from the malignant transformation of normal stem cells or progenitors and retain the capacity to both self-renew and produce mature progeny. Therefore, CSC are thought to possess the growth potential to reform tumors that is clinically recognized as disease relapse or progression. We have studied CSC in multiple myeloma (MM), a disease characterized by the clonal expasion of neoplastic plasma cells. Although plasma cells are the hallmark of the disease, we found that these cells are terminally differentiated and have limited replicative potential. Instead, MM plasma cells arise from a self-renewing CSC compartment that phenotypically resembles normal memory B cells. Our preliminary data demonstrate that MM CSC are relatively resistant to drugs currently used to clinically treat the disease and biologically distinct from MM plasma cells; these data may explain the typical clinical response pattern of MM patients to treatment (i.e., initial response followed by relapse and disease progression). Furthermore, we have found that cellular pathways which regulate cell fate decisions in normal stem cells are similarly active in MM CSC. We hypothesize that CSC are responsible for the long-term outcomes of patients with MM and that effective stem cell targeted strategies will lead to long-term remissions. Accordingly, we propose to: 1). Further characterize MM CSC and study their clinical relevance; and 2). Study the role of developmental signaling pathways in the regulation of MM CSC and their potential as therapeutic targets. PUBLIC HEALTH RELEVANCE: We previously demonstrated that clonogenic cells in multiple myeloma are not plasma cells that are typically associated with the disease, but rather mature B cells that appear to have the capacity to undergo self-renewal and give rise to terminally differentiated tumor cells (plasma cells). We propose to further characterize myeloma stem cells by correlating their frequency and growth potential with validated prognostic factors that predict clinical outcomes as well as investigate the role of developmental signaling pathways that include Hedgehog, Notch and Wnt, in regulating myeloma cancer stem cells.

描述（由申请人提供）：越来越多的证据表明，许多人类癌症由以分层方式组织的功能异质细胞组成，其中不太成熟的癌症干细胞（CSC）产生分化的肿瘤细胞。这些细胞类型之间的区别对于有效抗癌策略的开发具有重要意义，因为构成大多数细胞并在表型上表征疾病的成熟肿瘤细胞缺乏长期复制潜力。相比之下，罕见的 CSC 似乎是由正常干细胞或祖细胞的恶性转化产生的，并保留自我更新和产生成熟后代的能力。因此，CSC被认为具有改变临床上认为疾病复发或进展的肿瘤的生长潜力。我们研究了多发性骨髓瘤 (MM) 中的 CSC，这是一种以肿瘤性浆细胞克隆性扩张为特征的疾病。尽管浆细胞是该疾病的标志，但我们发现这些细胞是终末分化的并且复制潜力有限。相反，MM 浆细胞源自自我更新的 CSC 区室，其表型类似于正常记忆 B 细胞。我们的初步数据表明，MM CSC 对目前临床上用于治疗该疾病的药物具有相对耐药性，并且在生物学上与 MM 浆细胞不同；这些数据可以解释 MM 患者对治疗的典型临床反应模式（即初始反应，随后复发和疾病进展）。此外，我们发现正常干细胞中调节细胞命运决定的细胞途径在 MM CSC 中也同样活跃。我们假设 CSC 负责 MM 患者的长期预后，有效的干细胞靶向策略将带来长期缓解。因此，我们建议：1）。进一步表征 MM CSC 并研究其临床相关性；和2）。研究发育信号通路在 MM CSC 调节中的作用及其作为治疗靶点的潜力。公共卫生相关性：我们之前证明，多发性骨髓瘤中的克隆细胞不是通常与该疾病相关的浆细胞，而是成熟的 B 细胞，它们似乎具有自我更新的能力并产生终末分化的肿瘤细胞（浆细胞）。我们建议通过将骨髓瘤干细胞的频率和生长潜力与预测临床结果的经过验证的预后因素相关联来进一步表征骨髓瘤干细胞，并研究包括 Hedgehog、Notch 和 Wnt 在内的发育信号通路在调节骨髓瘤干细胞中的作用。