MicroRNA Targeted Therapeutic Approach for Pediatric High-Grade Glioma

MicroRNA 靶向治疗儿童高级别胶质瘤

• 批准号: 10043989
• 负责人: Tohru Yamada
• 金额: $ 41.11万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043989
• 关键词: Adult; Apoptosis; Attention; Binding; Biological Markers; Blood - brain barrier anatomy; Cell Cycle Arrest; Cell Cycle Progression; Cell membrane; Cells; Chemotherapy-Oncologic Procedure; Childhood Brain Neoplasm; Childhood Glioma; Childhood Malignant Brain Tumor; Clinic; Clinical; Cytoplasm; Data; Development; Disease; Face; Genes; Glioma; Goals; Growth; Human; Hybrids; Immune response; In Vitro; Lead; Location; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Messenger RNA; MicroRNAs; Normal Cell; Oligonucleotides; Oncogenic; Oxidation-Reduction; PTEN gene; Peptides; Property; Proteins; Pseudomonas aeruginosa; Resistance; Specificity; System; Therapeutic Agents; Tissues; Toxic effect; Transfection; Translations; Treatment Efficacy; Treatment-related toxicity; Tumor Suppressor Proteins; Xenograft procedure; base; brain tissue; cancer cell; cancer initiation; cancer therapy; chemical property; immunogenic; immunogenicity; improved; in vivo; innovation; macromolecule; mouse model; novel; overexpression; pathogen; pediatric patients; small molecule; targeted delivery; targeted treatment; therapeutic miRNA; tool; tumor; tumor growth; tumor progression

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.

摘要 癌症化疗已采取了各种策略，然而，治疗相关的毒性 和免疫应答仍然是主要问题，这是由于缺乏对癌细胞的靶向递送。在 特别地，儿科高级别胶质瘤（pHGG）目前通常难以治疗，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， 因此与pHGG的起始和进展密切相关。抗miRNA可以中和 在pHGG中异常表达的oncomiRNA，并恢复肿瘤的表达 抑制肿瘤生长的抑制蛋白。然而，目前，抗miRNA的细胞递送是不可能的。 这是进入临床的最大挑战之一。肽介导的抗miRNA 有效和特异性靶向癌细胞的递送可以提供解决方案。 我们的创新方法可能克服这些问题，原因如下： 新型无毒CPP，p28，选择性进入癌细胞; 2）p28穿过血脑屏障 并且当功能分子缀合时可以用作癌症靶向递送系统; 3） p28与抗miRNAs结合，对靶点具有高度特异性， 特异性抑制pHGG生长。 我们的支持数据表明，p28与抗miR 20缀合（抗miR 20-p28）， 与成人高级别胶质瘤（aHGG）和健康脑相比，pHGG中过表达的oncomiR 组织，优先并成功地将功能性抗miR 20递送到pHGG中。总目标 该建议的一个重要方面是采取战略性方法来评估抗miRNAs缀合物的作用， 用无毒的肿瘤靶向肽（p28）在pHGG上进行。如果成功，我们的方法可能 潜在地克服了目前基于抗miRNA的治疗的主要局限性，并改善了 治疗儿童脑肿瘤而不损害健康组织。