Nanoparticle Formulations of siRNA: The Next Generation of Targeted Therapy for Lymphomas and Leukemias?
Nanoparticle Formulations of siRNA: The Next Generation of Targeted Therapy for Lymphomas and Leukemias?
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siRNA 纳米颗粒制剂：下一代淋巴瘤和白血病靶向治疗？
DOI：
10.1016/j.ebiom.2014.11.013
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发表时间：
2014
期刊：
影响因子：
11.1
通讯作者：
Wang,AndrewZ
中科院分区：
文献类型：
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作者：
Wang,AndrewZ
许多液体肿瘤(淋巴瘤和白血病)具有特征性的基因组改变，这些改变对其疾病的发展和进展至关重要。例如，超过90%的慢性髓细胞白血病(CML)是由t(9；22)(q34；q11)或bcr/abl易位引起的，而超过75%的套细胞淋巴瘤有t(11，14)(q13，32)易位(KurzRock等人，2003年；Li等人，1999年)。由于这些基因组改变经常是肿瘤发生过程的驱动因素，抑制由此产生的异常信号通路的靶向治疗取得了显著的临床成功。伊马替尼抑制ABL酪氨酸激酶，被认为是第一批针对癌症的分子靶向疗法之一(Druker等人，2001年)。最近的一项研究表明，对伊马替尼长期有效的慢性粒细胞白血病患者的存活率与普通人群相似(Gambacorti-Passerini等人，2011年)。今天，许多针对淋巴瘤和白血病的靶向治疗正在临床上使用或正在开发中(Johnston等人，2010年；Byrd等人，2014年)。尽管靶向治疗取得了成功，但许多基因组改变被认为是“无法用药治疗的”。一个这样的例子是上述t(11，14)(q13，32)易位，它增加了细胞周期蛋白D1的表达(Musgrove等人，2011年)。这种不可药物靶标的另一个例子是CD22ΔE12，在乌肯等人的一篇研究论文中描述了这一点。在本期《生态生物医学》中(Uockun等人，2014)。生理上，CD22负向调节细胞增殖，CD22ΔE12缺失导致这种刹车的释放。作者证明CD22ΔE12与儿童和成人B前体急性淋巴细胞性白血病有关。更重要的是，他们表明，用小干扰RNA(SiRNA)敲除CD22siRNA E12会降低肿瘤细胞的克隆性，这表明该突变是导致BPL疾病进展的原因。然而，由于CD22ΔE12突变导致细胞通路上缺乏负面信号，因此它是一个无法药物治疗的靶点。尽管如此，正如作者所证明的那样，这种突变是可以通过siRNA进行治疗的。利用RNA干扰来治疗疾病的想法并不新鲜。如上所述，这种战略可以治疗被认为不可用药和具有深远潜力的目标。SiRNA临床翻译的关键挑战一直是药物递送。首先，siRNA需要优先传递给患病细胞，以避免对正常细胞的副作用。其次，siRNA需要进入靶细胞的胞浆
Many liquid tumors (lymphomas and leukemias) have characteristic genomic alterations that are critical to their disease development and progression. For example, greater than 90% of the chronic myelogenous leukemias (CML) are caused by the t (9; 22)(q34; q11) or BCR/ABL translocation, whereas more than 75% of mantle cell lymphomas have the t (11, 14)(q13, 32) translocation (Kurzrock et al., 2003; Li et al., 1999). Because these genomic alterations are frequently drivers of the oncogenesis process, targeted therapies that inhibit the resultant aberrant signaling pathways have achieved remarkable clinical success. Imatinib, which inhibits the ABL tyrosine kinase, is considered one of the first molecularly targeted therapies for cancer (Druker et al., 2001). A recent study suggested that patients with CML that are long-term responders to imatinib have similar survival as the general population (Gambacorti-Passerini et al., 2011). Today, many targeted therapies are in clinical use or are under clinical development for the treatment of lymphomas and leukemias (Johnston et al., 2010; Byrd et al., 2014). Despite the success of targeted therapies, many genomic alterations are considered “undruggable”. One such example is the abovementioned t (11, 14)(q13, 32) translocation, which increases the expression of cyclin D1 (Musgrove et al., 2011). Another example of such an undruggable target is CD22ΔE12, described in a research paper by Uckun et al. in this issue of EBioMedicine (Uckun et al., 2014). Physiologically, CD22 negatively regulates cellular proliferation, and the CD22ΔE12 deletion results in the release of this brake. The authors demonstrated that CD22ΔE12 is associated with both pediatric and adult B-precursor acute lymphoblastic leukemias (BPL). More importantly, they showed that knockdown of CD22ΔE12 with small interfering RNA (siRNA) decreased the tumor cells' clonogenicity, suggesting that the mutation is responsible for disease progression in BPL. However, because the CD22ΔE12 mutation results in the lack of negative signaling on cellular pathways, it is an undruggable target. Despite this, the mutation is amenable to treatment by siRNA, as demonstrated by the authors.The idea of utilizing RNA interference for the treatment of diseases is not new. As mentioned above, such a strategy can treat targets that are considered undruggable and with far-reaching potential. The key challenge in siRNA clinical translation has been drug delivery. First, siRNAs need to be preferentially delivered to diseased cells to avoid side effects to normal cells. Second, siRNA needs to enter the target cells' cytosol