Targeting Cancer Stem Cells

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-肿瘤浆细胞(PC)-复制潜力有限；相反，MM PC实际上来自类似记忆B细胞的自我更新的癌症干细胞。然而，关于癌症干细胞的临床相关性的数据有限。我们发现新型抗MM药物Bortezomib(Velade)和来那度胺(Revlimid)在体外对MM PC有抑制作用，但对MM干细胞几乎没有作用。相反，利妥昔单抗和阿伦图珠单抗在体外消除了MM干细胞，但对缺乏相关靶抗原(分别为CD20和CD52)的MM PC没有活性。此外，我们和其他人已经证明，伊马替尼对慢性粒细胞白血病(CML)干细胞几乎没有活性，尽管对来自同一患者的承诺的CML祖细胞具有强大的活性。因此，即使启动致癌事件是靶点，如伊马替尼和bcr-abl，干细胞的固有特性也可能使靶点无法获得或对细胞生存没有必要。因此，对伊马替尼(bcr-abl的聚合酶链式反应阴性)反应最好的CML患者，即使不是总是在停药时也会复发，尽管仍在继续服药，但许多患者仍有进展的证据。目前的许多癌症治疗方法主要针对构成大部分肿瘤的分化癌细胞，而不是负责维持肿瘤的罕见癌症干细胞。这种疗法可能会产生戏剧性的反应，但如果癌症干细胞 负责维持疾病的人也不是有针对性的。同样重要的是，如果仅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，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探索在实验室中针对多发性骨髓瘤和髓系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临床。因此，本项目同时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出在实验室和临床上研究这些稀有细胞的新方法。

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.