Targeting Cancer Stem Cells

靶向癌症干细胞

• 批准号: 8258342
• 负责人: RICHARD J JONES
• 金额: $ 37.04万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258342
• 关键词: Antigen Targeting; Bone Marrow Transplantation; Bortezomib; CD20 Antigens; CDW52 gene; Cell Survival; Cells; Chronic Myeloid Leukemia; Clinic; Clinical; Clinical Trials; Commit; Cyclophosphamide; Data; Development; Disease; Disease remission; Dose; Event; Imatinib; In Vitro; Interferons; Interleukin-6; Laboratories; Laboratory Study; Maintenance; Malignant Neoplasms; Memory B-Lymphocyte; Methodology; Multiple Myeloma; Myeloid Leukemia; Myeloproliferative disease; Neoplastic Plasma Cell; Oncogenic; Patients; Pharmaceutical Preparations; Plasma Cells; Property; Publications; Relapse; Revlimid; Stem cells; Translating; Translations; Treatment Failure; Velcade; alemtuzumab; bcr-abl Fusion Proteins; cancer cell; cancer stem cell; cancer therapy; clinically relevant; clinically significant; human disease; lenalidomide; novel; progenitor; response; rituximab; self-renewal; treatment effect; tumor

Cancer stem cells have recently been identified in several different malignancies. An example is our finding that the hallmark of multiple myeloma (MM), the neoplastic plasma cells (PC), have limited replicative potential; rather, the MM PC actually arise from self-renewing cancer stem cells that resemble memory B cells. Yet, there have been limited data on the clinical relevance of cancer stem cells. We found that the novel anti-MM agents bortezomib (velcade) and lenalidomide (revlimid) inhibited MM PC but had little activity against MM stem cells in vitro. Conversely, rituximab and alemtuzumab eliminated MM stem cells in vitro, but had no activity against MM PC that lack the relevant target antigens (CD20 and CD52, respectively). In addition, we and others have shown that imatinib has little to no activity against chronic myeloid leukemia (CML) stem cells, despite having potent activity against committed CML progenitors from the same patients. Thus, even when the initiating oncogenic event is targeted, as with imatinib and BCR-ABL, inherent properties of stem cells may make the target inaccessible or unnecessary for cell survival. Accordingly, CML patients with the best responses to imatinib (PCR negativity for BCR-ABL) often, if not invariably, relapse when the drug is discontinued, and many have evidence of progression despite remaining on the drug. Many current therapies for cancer primarily target differentiated cancer cells that constitute the bulk of the tumor mass, rather than the rare cancer stem cells responsible for tumor maintenance. Such therapies may produce dramatic responses, but are unlikely to result in long-term remissions if the cancer stem cells responsible for maintaining the disease are also not targeted. Just as importantly, therapy directed against targets uniquely expressed by cancer stem cells might be prematurely abandoned if clinical activity is judged solely by standard response criteria that reflect the effects of treatment on the bulk of the cancer. The overall objective of this project is to explore approaches in the laboratory that target cancer stem cells in MM and myeloid malignancies, and translate promising treatments to the clinic. Thus, both laboratory studies and novel clinical trials are proposed in this project. Successful translation will require the development of novel methodologies for studying these rare cells both in the laboratory and clinically.

最近在几种不同的恶性肿瘤中发现了癌症干细胞。一个例子是我们发现多发性骨髓瘤（MM），肿瘤浆细胞（PC）的标志具有有限的复制潜力。相反，MM PC实际上是由类似于记忆B细胞的自我更新的癌症干细胞引起的。然而，关于癌症干细胞的临床相关性数据有限。我们发现，新型的抗MM硼替佐米（Velcade）和Lenalidomide（Revlimid）抑制了MM PC，但在体外对MM干细胞的活性很小。相反，利妥昔单抗和Alemtuzumab在体外消除了MM干细胞，但对缺乏相关靶抗原的MM PC没有活性（分别为CD20和CD52）。此外，我们和其他人表明，伊马替尼对慢性髓样白血病（CML）干细胞几乎没有活性，尽管对同一患者的CML祖细胞具有有效的活性。 因此，即使对伊马替尼和BCR-ABL的启动致癌事件的靶向，干细胞的固有特性也可能使靶标的无法接近或不需要细胞存活。因此，对伊马替尼反应最佳的CML患者（BCR-ABL的PCR负性）经常（即使不是始终）停止药物时复发，许多人尽管仍保留该药物，许多人仍具有进展的证据。许多目前的癌症疗法主要靶向构成肿瘤肿块大部分的分化癌细胞，而不是负责肿瘤维持的稀有癌症干细胞。这种疗法可能会产生戏剧性的反应，但是如果癌症干细胞 负责维持疾病的负责也不是针对性的。同样重要的是，针对由癌症干细胞唯一表达的靶标的治疗可能会过早地放弃，如果仅根据反映治疗对大部分癌症的影响的标准反应标准来判断临床活动。该项目的总体目的是探索实验室中针对MM和髓样恶性肿瘤的癌症干细胞的方法，并将有希望的治疗方法转化为诊所。因此，在该项目中提出了实验室研究和新颖的临床试验。成功的翻译将需要开发新的方法论，以在实验室和临床上研究这些稀有细胞。