目前有关靶标RNA的药物发展存在着有许多未解决的问题。例如，这种药物在肿瘤细胞中积累到足够程度是否会产生治疗效果呢？什么样的RNA是很好的靶标呢？我们是否可以选择性地针对一些全身给药的肿瘤细胞呢？这些药物是否具有一些重大的长期副作用？以下两篇研究报道使我们对解决这些问题的理解又跨近了一大步。
Mark Davis等人报道的研究结果是关于对传统治疗方法很难治愈的实体瘤病人进行CALAA-01全身用药的I期临床试验的。
CALAA-01是一种纳米颗粒性的药物，它包含有靶标核糖核苷还原酶M2（RRM2）的小分子干扰RNA。除此之外，纳米颗粒的表面包含转铁蛋白，它是转铁蛋白受体的配体，在肿瘤细胞中表达下调。作者从黑色素瘤患者身上获得肿瘤切片样本，并且这些患者每个人都接受了不同剂量的CALAA-01。研究表明，这种纳米颗粒能以剂量依赖的方式定位在肿瘤细胞上，而不是定位在正常表皮附近。同时RRM2在mRNA和蛋白质水平上的表达都下降了。他们的研究也表明在患者的肿瘤切片样本中RNA干扰的通路被激活了。尽管这种药物的药效还没有被充分证实，但是切片样本的分析结果已经显示这种RNA干扰效用可以持续几个星期。
因此，是否有其它类型的RNA能有效地在肿瘤中沉默呢？Li Ma等人证实了antagomir-10b的全身用药的药效，antagomir-10b是一种能沉默microRNA miR-10b的反义核苷酸。miR-10b是由转录因子TWIST1诱导产生的，并能靶标HOXD10 mRNA，同时能相应地增加RHOC的表达。miR-10b的表达与高级别的肿瘤和转移相关，尤其是在乳腺癌，胰腺癌和胶质母细胞瘤。
高水平地表达TWIST1和miR-10b的4T1小鼠乳腺肿瘤细胞在同系基因型小鼠中的正位移植，产生了能转移到肺部的原发性肿瘤。作者发现，antagomir-10b的全身用药对于原发性肿瘤的大小和生长几乎没有影响，但是可以在很大程度上降低肿瘤的转移数目。除此之外，作者发现在antagomir-10b用药的小鼠的原发性肿瘤中HOXD10的表达水平升高了，但是其它的microRNA（包括miR-10a，与miR-10b只有一个核苷酸的差异）的表达水平不受影响。在正位注射之前沉默掉antagomir-10b用药的小鼠的4T1细胞中的miR-10b，能显著降低转移的数目（原发性肿瘤生长仍然不受影响），这表明antagomir-10b的抗转移效用作用于肿瘤细胞中而不是肿瘤细胞的微环境。当省略了转移的侵袭和血管内渗步骤，将4T1细胞直接注射到鼠的尾部血管上后，研究人员发现应用antagomir-10b治疗并不能抑制转移性肿瘤的生长。最后，使用antagomir-10b进行全身注射后，作者检测了这种药物对注射相同剂量的antagomir-10b正常小鼠毒力影响，发现并没有明显的差别。
因此，靶标RNA的抗癌治疗似乎让我们向寻找一类新的抗癌药物跨近了一步。
生物探索推荐英文原文：
There are many unanswered questions about the development of drugs that target RNAs. For example, will such drugs accumulate to a sufficient extent in tumour cells to produce a therapeutic effect? What RNAs are good targets? Can we selectively target tumour cells with systemically administered drugs? Will there be significant long-term side effects? This month, two papers report findings that take us closer to answering some of these questions.
Mark Davis and colleagues report the initial findings of a Phase I clinical trial of systemic administration of CALAA-01 in patients with solid tumours that are refractory to standard therapy. CALAA-01 is a nanoparticle drug containing small interfering RNAs targeted to ribonucleoside reductase M2 (RRM2). In addition, on its surface the nanoparticle displays transferrin, which is a ligand for transferrin receptors that are often upregulated on tumour cells. The authors took tumour biopsy samples from three patients with metastatic melanoma, and each patient received a different dose of CALAA-01. They showed that the nanoparticles localized in the tumour cells — but not the surrounding normal epidermis — in a dose-dependent manner, and that RRM2 mRNA and protein levels were reduced. They also found evidence of RNA interference pathway activation in biopsy samples from one patient. Although the pharmacodynamics of this drug are still to be fully characterized, the biopsy analyses suggest that the RNA interference effects could last several weeks.
So, can other types of RNA be therapeutically silenced in tumours? Li Ma and colleagues report the effects of systemic administration of antagomir-10b, an antisense oligonucleotide that silences the microRNA miR-10b. miR-10b is induced by the transcription factor TWIST1 and targets HOXD10 mRNA, which consequently increases the expression of RHOC. The expression of miR-10b has been associated with high-grade tumours and metastases, particularly in breast carcinoma, pancreatic adenocarcinoma and glioblastoma.
Orthotopic transplantation of 4T1 mouse mammary tumour cells, which express high levels of TWIST1 and miR-10b, in syngeneic mice produces primary tumours that metastasize to the lungs. The authors found that systemic administration of antagomir-10b had little effect on the size and growth of the primary tumour but significantly reduced the number of metastases. Moreover, the authors found that HOXD10 levels increased in primary tumours from mice treated with antagomir-10b, but levels of other microRNAs (including miR-10a, which differs from miR-10b by one nucleotide) were unaffected. Silencing of miR-10b in 4T1 cells prior to orthotopic injection also significantly decreased the number of metastases (primary tumour growth remained unaffected) indicating that the anti-metastatic effects of antagomir-10b occur in the tumour cells rather than the tumour microenvironment. They also found that treatment with antagomir-10b did not suppress metastatic tumour growth when 4T1 cells were injected in the tail vein, which bypasses the invasion and intravasation steps of metastasis. Finally, given that antagomir-10b was systemically administered the authors assessed the toxicity to normal mice treated with the same dosing schedule of antagomir-10b; they found no substantial effects.
Therefore, anticancer therapies that target RNAs seem to be one step closer to being a new class of anticancer drug.
