Role of multiple myeloma cancer stem cells in clinical disease

描述（由申请人提供）：成熟浆细胞包括多发性骨髓瘤（MM）的大部分肿瘤细胞，但我们最近报道这些细胞在体外或体内几乎没有克隆生长潜力。相反，我们发现MM的生长是由克隆相关的记忆B细胞驱动的，这些细胞能够在免疫缺陷小鼠中再现疾病，并且对标准的抗MM治疗具有相对的抵抗力。这些功能特性表明，这些克隆型B细胞是MM癌干细胞（CSC），并在疾病复发和进展中发挥核心作用。然而，目前尚不清楚我们的实验室研究结果是否适用于该疾病的发病机制，因为在MM或任何人类恶性肿瘤中几乎没有数据表明CSCs实际上与临床相关。证明CSCs频率和/或持续性的变化与临床结果相关，或证明靶向和抑制CSCs可提高生存率，将为其临床相关性提供最有力的证据，并促进其进一步研究。为此，我们开发了能够在治疗过程中连续量化MM CSC的实验室检测方法，我们的早期数据表明MM CSC频率的变化与无进展生存期相关。我们还确定了基于CD20表达和端粒酶活性增强的MM CSC靶向策略，并利用抗CD20抗体利妥昔单抗和新型端粒酶抑制剂伊美特司他启动了试点临床试验。尽管这些早期试验的临床活性有限，但我们相关研究的结果为基于抗cd20和端粒酶抑制剂的MM治疗方法提供了重要的见解，并使我们能够修改这些方法。该项目的总体目标是确定MM CSCs是否具有临床相关性，我们相信，我们以前的研究现在使我们处于一个理想的位置，通过将其频率与临床结果相关联，并确定新型CSCs靶向策略的临床影响，来解决这个问题。这些发现可能对MM和CSC领域具有重要意义，我们建议：1)。检查MM CSC频率与接受治疗状态的患者临床结果之间的关系；2）. 确定B细胞定向放射免疫治疗MM的效果；和3)。测定MM端粒酶抑制活性。

DESCRIPTION (provided by applicant): 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.