MicroRNA Targeted Therapeutic Approach for Pediatric High-Grade Glioma

MicroRNA 靶向治疗儿童高级别胶质瘤

基本信息

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
项目类别：
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

项目摘要

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.

抽象的癌症化疗已采取各种策略，然而，与治疗相关的毒性由于缺乏对癌细胞的靶向递送，免疫反应仍然是主要问题。在特别是，儿童高级别胶质瘤（pHGG）目前通常难以治疗，很大程度上是由于发病部位。高水平的致癌 miRNA (oncomiR) 抑制肿瘤抑制蛋白的表达，因此，它与 pHGG 的启动和进展密切相关。抗 miRNA 可以中和 pHGG中异常表达的oncomiRNA，恢复肿瘤的表达抑制肿瘤生长的抑制蛋白。然而，目前抗 miRNA 的细胞递送进入临床的最大挑战之一。肽介导的抗 miRNA 有效且特异性地针对癌细胞的递送可能提供一种解决方案。我们的创新方法有可能克服这些问题，原因如下：1）a 新型无毒CPP，p28，选择性进入癌细胞； 2）p28穿过血脑屏障当功能分子缀合时，可以作为癌症靶向递送系统； 3） p28 与抗 miRNA 缀合，对其靶点具有高度特异性，预计将特异性抑制 pHGG 的生长。我们的支持数据表明，p28 与抗 miR20（抗 miR20-p28）缀合，与成人高级神经胶质瘤 (aHGG) 和健康大脑相比，pHGG 中 oncomiR 过度表达组织，优先并成功地将功能性抗 miR20 传递到 pHGG 中。总体目标该提案的目的是采取战略方法来评估抗 miRNA 缀合的效果 pHGG 上含有无毒肿瘤靶向肽 (p28)。如果成功的话，我们的方法可能会可能克服当前基于抗 miRNA 的疗法的主要局限性并改善治疗儿童脑肿瘤而不损害健康组织。