Role of multiple myeloma cancer stem cells in clinical disease

摘要 在多发性骨髓瘤(MM)中，成熟浆细胞占肿瘤细胞的大多数，但我们最近报道 无论是在体外还是在体内，这些细胞几乎没有克隆生长潜力。相反，我们发现MM 生长是由克隆相关的记忆B细胞推动的，这些B细胞能够重现疾病 免疫缺陷的小鼠，对标准的抗MM疗法具有相对的抵抗力。这些功能属性 提示这些克隆型B细胞是多发性骨髓瘤肿瘤干细胞(CSC)，在疾病中起中心作用 复发和进展。然而，目前尚不清楚我们的实验室发现是否适用于 由于MM或任何人类恶性肿瘤中存在的数据很少，因此CSCs实际上与临床相关。 CSCs频率和/或持续性的改变与临床相关的证据 结果或靶向和抑制CSCs提高存活率将提供 为它们的临床相关性提供了最有力的证据，并促进了它们的进一步研究。为此，我们有 开发了能够在治疗过程中连续定量MM CSCs的实验室分析方法 我们的早期数据表明，多发性骨髓间充质干细胞频率的变化与无进展生存率有关。 我们还根据其CD20和增强型CD20的表达确定了MM CSC的靶向策略 端粒酶活性，并利用抗CD20抗体利妥昔单抗和新的 端粒酶抑制剂伊美司他。尽管在这些早期阶段的试验中临床活动有限，但我们的研究结果 相关研究为基于抗CD20和端粒酶抑制剂的研究提供了重要的见解 MM中的方法，并允许我们修改这些方法。这个项目的总体目标是确定 多发性骨髓间充质干细胞是否与临床相关，我们相信，我们之前的研究现在将我们置于 通过将它们的频率与临床结果相关联以及 确定新的CSC靶向策略的临床影响。这些发现可能具有重要的意义 对MM和CSC领域的一般影响，我们建议：1)。审视这一关系 多发性骨髓间充质干细胞的频率与治疗状态患者的临床结果之间的关系； 确定B细胞定向放射免疫治疗对多发性骨髓瘤的疗效；确定…的活动 MM中的端粒酶抑制作用

ABSTRACT Mature plasma cells comprise the majority of tumor cells in multiple myeloma (MM), but we recently reported that these cells have little to no clonogenic growth potential either in vitro or in vivo. Instead, we found that MM growth was driven by clonally related memory B cells that are capable of recapitulating disease in immunodeficient mice and are relatively resistant to standard anti-MM therapies. These functional properties suggest that these clonotypic B cells are MM cancer stem cells (CSC) and play a central role in disease relapse and progression. However, it is unclear whether our laboratory findings apply to the pathogenesis of the disease since little data exists in MM or any human malignancy that CSCs are actually clinically relevant. Proof that the changes in the frequency and/or persistence of CSCs are associated with clinical outcomes or that the targeting and inhibition of CSCs improves survival rates would provide the strongest evidence for their clinical relevance and promote their further study. To this end, we have developed laboratory assays that are capable of serially quantifying MM CSCs over the course of treatment and our early data suggest that changes in MM CSC frequency are associated with progression free survival. We have also identified MM CSC targeting strategies based on their expression of CD20 and enhanced telomerase activity and have initiated pilot clinical trials utilizing the anti-CD20 antibody rituximab and the novel telomerase inhibitor imetelstat. Although clinical activity was limited in these early phase trials, results from our correlative studies have provided important insights regarding anti-CD20 and telomerase inhibitor based approaches in MM and allowed us to modify these approaches. The overall goal of this project is to determine whether or not MM CSCs are clinically relevant, and we believe that our previous studies now place us in an ideal position to address this question by both correlating their frequency with clinical outcomes and determining the clinical impact of novel CSC-targeting strategies. These findings may have important implications for both MM and the CSC field in general, and we propose to: 1). Examine the relationship between MM CSC frequency and clinical outcomes in patients treated with state of the therapies; 2). Determine the effects of B cell directed radioimmunotherapy in MM; and 3). Determine the activity of telomerase inhibition in MM.