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）的标志，即肿瘤性浆细胞（PC），具有有限的复制潜力;相反，MM PC实际上是由类似记忆B细胞的自我更新癌症干细胞产生的。然而，关于癌症干细胞的临床相关性的数据有限。我们发现，新的抗MM药物硼替佐米（万珂）和来那度胺（revlimid）抑制MM PC，但在体外对MM干细胞几乎没有活性。相反，利妥昔单抗和阿仑单抗在体外消除了MM干细胞，但对缺乏相关靶抗原（分别为CD 20和CD 52）的MM PC没有活性。此外，我们和其他人已经表明，伊马替尼对慢性粒细胞白血病（CML）干细胞几乎没有活性，尽管对来自相同患者的定型CML祖细胞具有有效活性。 因此，即使当起始致癌事件被靶向时，如伊马替尼和BCR-ABL，干细胞的固有特性也可能使靶点无法接近或对细胞存活是不必要的。因此，对伊马替尼有最佳反应的CML患者（BCR-ABL的PCR阴性）在停药时经常（如果不是总是）复发，许多患者尽管仍在使用药物，但仍有进展的证据。目前的许多癌症疗法主要针对构成肿瘤块的大部分的分化癌细胞，而不是负责肿瘤维持的罕见癌症干细胞。这种疗法可能会产生戏剧性的反应，但不太可能导致长期缓解，如果癌症干细胞， 负责维持疾病的人也没有针对性。同样重要的是，如果仅通过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性，则针对癌症干细胞独特表达的靶点的治疗可能会过早放弃。该项目的总体目标是在实验室中探索靶向MM和骨髓恶性肿瘤中的癌症干细胞的方法，并将有希望的治疗方法转化为临床。因此，本项目提出了实验室研究和新的临床试验。成功的翻译将需要开发新的方法来研究这些罕见的细胞在实验室和临床上。