Role of multiple myeloma cancer stem cells in clinical disease

多发性骨髓瘤癌症干细胞在临床疾病中的作用

• 批准号: 8628225
• 负责人: CAROL A HUFF
• 金额: $ 58.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628225
• 关键词: 90Y; Address; Aftercare; Autologous Stem Cell Transplantation; B-Lymphocytes; Biological Assay; Cells; Characteristics; Clinic; Clinical; Clinical Treatment; Clinical Trials; Correlative Study; Cyclophosphamide; Data; Disease; Dose; Drug resistance; Flow Cytometry; Frequencies; Generations; Goals; Growth; Human; Ibritumomab Tiuxetan; Immunodeficient Mouse; In Vitro; Laboratories; Laboratory Finding; Length; MS4A1 gene; Malignant Neoplasms; Memory B-Lymphocyte; Methods; Monoclonal Antibody CD20; Multiple Myeloma; Nature; Newly Diagnosed; Outcome; Pathogenesis; Patients; Phase; Phase I Clinical Trials; Plasma Cells; Play; Positioning Attribute; Progression-Free Survivals; Progressive Disease; Property; Radioimmunotherapy; Recurrent disease; Regimen; Relapse; Reporting; Resistance; Role; Specimen; Staging; Surface Antigens; Survival Rate; Targeted Radiotherapy; Telomerase; Telomerase Inhibitor; Telomerase inhibition; Therapeutic Agents; Translating; Transplantation; base; cancer stem cell; cell type; clinical efficacy; clinically relevant; experience; improved; in vivo; insight; lenalidomide; neoplastic cell; novel; phase 2 study; public health relevance; response; rituximab; self-renewal; telomere; tositumomab; tumor; tumorigenic

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.

摘要 成熟浆细胞构成多发性骨髓瘤（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 生长是由克隆相关的记忆B细胞驱动的，这些细胞能够重现疾病， 在免疫缺陷小鼠中，抗MM抗体对标准抗MM疗法具有相对抗性。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研究结果是否适用于 由于在MM或任何人类恶性肿瘤中几乎没有数据表明CSC实际上具有临床相关性，因此该疾病。 证明CSC频率和/或持续性的变化与临床 结果或靶向和抑制CSC提高存活率将提供 为它们的临床意义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 开发了能够在治疗过程中连续定量MM CSC的实验室测定 我们的早期数据提示MM CSC频率的变化与无进展生存期相关。 我们还确定了基于其CD 20表达的MM CSC靶向策略，并增强了其免疫原性。 端粒酶活性，并已启动试点临床试验，利用抗CD 20抗体利妥昔单抗和新的 端粒酶抑制剂伊美司他。尽管这些早期试验的临床活性有限，但我们的研究结果显示， 相关的研究提供了关于抗CD 20和端粒酶抑制剂的重要见解， MM的方法，并允许我们修改这些方法。本项目的总体目标是确定 无论MM CSC是否具有临床相关性，我们相信我们以前的研究现在将我们置于一个新的研究领域。 通过将其频率与临床结果相关联， 确定新型CSC靶向策略的临床影响。这些发现可能具有重要意义 的MM和CSC领域的影响一般，我们建议：1）。检查关系 MM CSC频率与接受治疗状态的患者的临床结局之间的关系; 2）。 确定B细胞定向放射免疫治疗在MM中的作用;和3）。确定的活动 MM中端粒酶抑制。