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。例如，我们发现多发性骨髓瘤（MM）的标志，肿瘤浆细胞（PC）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。我们发现新型抗MM药物硼替佐米（velcade）和来那度胺（revlimid）在体外抑制MM PC，但对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，我们和其他人已经表明，伊马替尼对慢性髓性白血病（CML）干细胞几乎没有活性，尽管对来自同一患者的慢性髓性白血病祖细胞有强有力的活性。因此，即使靶向起始致癌事件，如伊马替尼和BCR-ABL，干细胞的固有特性也可能使目标无法进入或不需要细胞存活。因此，对伊马替尼（BCR-ABL PCR阴性）反应最好的CML患者在停药后经常（如果不是总是）复发，而且许多患者在继续服用该药后仍有进展的迹象。许多目前的癌症治疗主要针对构成肿瘤肿块的大部分分化癌细胞，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，但如果癌症干细胞被破坏，则不太可能导致长期缓解

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.