MicroRNA Targeted Therapeutic Approach for Pediatric High-Grade Glioma

摘要 对于癌症化疗已经采取了各种策略，然而，与治疗相关的毒性 由于缺乏针对癌细胞的靶向传递，免疫反应仍然是主要问题。在……里面 特别是，儿童高级别胶质瘤(PHGG)目前通常很难治疗，主要是由于 疾病的位置。 高水平的致癌miRNA(OncomiR)抑制肿瘤抑制蛋白的表达， 因此在PHGGS的发生和发展中起着至关重要的作用。抗miRNA可以中和 在PHGG中异常表达的肿瘤iRNA，并恢复肿瘤的表达 抑制肿瘤生长的抑制蛋白。然而，抗miRNA的细胞递送目前是 进入临床的最大挑战之一。多肽介导的抗miRNA 高效且特定靶向癌细胞的递送可能提供一种解决方案。 我们的创新方法可能克服这些问题，原因如下：1)a) 新型无毒CPP，p28，选择性进入癌细胞；2)p28跨越血脑屏障 当功能分子连接时，可作为癌症靶向递送系统；3) P28-与高度特异的抗miRNAs结合将有望 特异性地抑制PHGGs的生长。 我们的支持数据表明，p28与抗miR20(抗miR20-p28)结合， PHGG中过表达的肿瘤与成人高级别胶质瘤(AHGG)和正常脑组织的比较 组织，优先并成功地将功能性抗miR20转移到PHGGs中。总目标 这项建议的目的是采取一种战略方法来评估结合的抗miRNAs的效果 在PHGGs上加入无毒的肿瘤靶向肽(P28)。如果成功，我们的方法可能会 有可能克服目前基于miRNA的抗治疗的主要限制，并改进 在不损害健康组织的情况下治疗儿童脑瘤。

ABSTRACT Various strategies have been taken for cancer chemotherapy, however, treatment-related toxicity and immune response are still major issues due to the lack of targeted delivery to cancer cells. In particular, pediatric high grade gliomas (pHGGs) are currently often difficult to treat, largely due to locations of the disease. High levels of oncogenic miRNA (oncomiR) inhibit expression of tumor suppressor proteins, thus critically implicated in initiation and progression of pHGGs. Anti-miRNA can neutralize oncomiRNA that are aberrantly expressed in pHGG, and restore the expression of tumor suppressor proteins that inhibit tumor growth. However, cellular delivery of anti-miRNA is currently one of the largest challenges for advancement into the clinic. Peptide-mediated anti-miRNA delivery that efficiently and specifically targets cancer cells may offer a solution. Our innovative approach potentially overcomes these problems for the following reasons: 1) a novel non-toxic CPP, p28, selectively enters cancer cells; 2) p28 crosses the blood-brain barrier and can serve as a cancer-targeting delivery system when functional molecules are conjugated; 3) p28-conjugated with anti-miRNAs, which is highly specific to their targets, will be expected to specifically inhibit growth of pHGGs. Our supporting data suggest that p28 conjugated with anti-miR20 (anti-miR20-p28), the overexpressed oncomiR in pHGG compared to adult high-grade glioma (aHGG) and healthy brain tissue, preferentially and successfully delivers functional anti-miR20 into pHGGs. The overall goal of this proposal is to take a strategic approach to evaluate the effects of anti-miRNAs conjugated with non-toxic tumor-targeting peptide (p28) on pHGGs. If successful, our approaches may potentially overcome the major limitation of current anti-miRNA-based therapy and improve the treatment of childhood brain tumors without damaging healthy tissues.