Cancer Stem Cell Targeting in Multiple Myeloma

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，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开发有效的抗癌策略具有重要意义，因为形成大多数细胞和疾病表型特征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，并且保留了自我更新和产生成熟后代的能力。因此，CSC被认为具有生长潜力，可以改造临床公认为疾病复发或进展的肿瘤。我们研究了多发性骨髓瘤（MM）中的CSC，这是一种以肿瘤浆细胞克隆扩增为特征的疾病。虽然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，复制潜力有限。相反，MM浆细胞起源于自我更新的CSC隔室，其表型类似于正常的记忆B细胞。我们的初步数据表明，MM CSC对目前用于临床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（即最初的反应随后是复发和疾病进展）。此外，我们发现在正常干细胞中调节细胞命运决定的细胞通路在MM CSC中同样活跃。我们假设CSC对MM患者的长期预后负责，而有效的干细胞靶向策略将导致长期缓解。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调控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原细胞不是与该疾病典型相关的浆细胞，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）。我们建议通过将其频率和生长潜力与预测临床结果的有效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癌症干细胞中的作用。

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.