Exosomes in Cancer Therapy

外泌体在癌症治疗中的应用

基本信息

批准号：
9230198
负责人：
RAGHU KALLURI
金额：
$ 38.41万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-27 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9230198
关键词：
Apoptosis Applications Grants Biological Assay Biology Blood Circulation Brain CD47 gene Cell Proliferation Cells Clinic Clinical Codon Nucleotides Complement Coupled Cultured Cells DNA Data Disease Eating Electroporation Endopeptidase K Engineering Exhibits Extracellular Protein Fibroblasts Frequencies Future Genetic Genetic study Genetically Engineered Mouse Glycine Half-Life Human ITGAM gene Image Impairment Integrins Investigation KRAS2 gene Label Liposomes Liver Lung Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator of activation protein Molecular Mus Mutation Oncogenic Pancreas Pancreatic Ductal Adenocarcinoma Pathogenesis Pathway interactions Patients Performance Phagocytes Pharmaceutical Preparations Pharmacology Physiological Play Process Proteins Proteomics RNA RNA Interference Research Role Route Signal Transduction Small Interfering RNA Survival Rate System Techniques Tertiary Protein Structure Testing Therapeutic Tissues Trypsin Western Blotting Xenograft procedure base cancer therapy design dosage effective therapy exosome experimental study extracellular vesicles imaging modality improved insight knowledge translation macrophage monocyte mouse model nanoparticle neutralizing antibody novel strategies novel therapeutics outcome forecast pancreatic cancer cells pancreatic neoplasm penis foreskin pre-clinical preclinical study programs small hairpin RNA standard of care therapeutic evaluation tumor tumor progression

项目摘要

Pancreatic Ductal Adenocarcinoma (PDAC) has a dismal prognosis with a median survival of about 6 months for patients with metastatic disease despite the use of current treatments. Therefore, PDAC is in urgent need of effective therapies. About 80% of PDAC patients exhibit mutation in KRAS, with substitution of a glycine residue at codon 12, such as KRASG12D, observed in high frequency. Many studies in mice unequivocally show that direct inhibition oncogenic KRAS significantly suppresses tumor progression. Despite such compelling evidence for the functional role of oncogenic KRAS in the PDAC pathogenesis, direct targeting of oncogenic KRAS has been elusive and it has often been dubbed as ‘undruggable’. In this grant application, we propose to explore a novel approach to target oncogenic KRAS using physiological nanoparticles known as exosomes. Exosomes are 40-150 nm extracellular vesicles (EVs) that contain DNA, RNA and proteins, and can deliver their contents efficiently into cells they fuse with and/or enter. Exploiting this unique feature of exosomes, our research team proposes in this grant application to test the central hypothesis that ‘exosomes can be engineered to deliver RNA interference (RNAi) molecules to target KRASG12D in pancreatic cancer’. Successful completion of the proposed studies will determine whether exosomes exhibit a superior ability to deliver RNAi molecules for the treatment of pancreatic cancer when compared to liposomes. Additionally, after such increased ability is investigated using multiple experimental systems, the proposal will further identify mechanism/s associated with the enhanced efficacy of exosomes in the delivery of RNAi molecules. Collectively, the proposal is designed to enable in-depth pre-clinical studies coupled with an investigation into the unique mechanism of action of exosomes to potentially facilitate future therapeutic testing in patients with PDAC.

胰腺导管腺癌 (PDAC) 预后不佳，中位生存期约为 6 个月对于尽管使用现有治疗方法仍患有转移性疾病的患者来说，PDAC 是迫切需要的。约 80% 的 PDAC 患者表现出 KRAS 突变，并被甘氨酸取代。许多小鼠研究明确表明，密码子 12 处存在残基，例如 KRASG12D。直接抑制致癌 KRAS 可以显着抑制肿瘤进展。致癌 KRAS 在 PDAC 发病机制中的功能作用的证据，直接靶向致癌基因 KRAS 一直难以捉摸，经常被称为“不可成药”，在本次拨款申请中，我们建议：探索一种使用称为外泌体的生理纳米粒子来靶向致癌 KRAS 的新方法。外泌体是 40-150 nm 的细胞外囊泡 (EV)，含有 DNA、RNA 和蛋白质，可以递送利用外泌体的这一独特功能，将它们的内容物有效地融入到它们融合和/或进入的细胞中。研究小组在这项拨款申请中提出测试“外泌体可以被旨在传递 RNA 干扰 (RNAi) 分子以靶向胰腺癌中的 KRASG12D”。拟议研究的成功完成将确定外泌体是否表现出卓越的能力与脂质体相比，另外还可以递送 RNAi 分子来治疗胰腺癌。使用多个实验系统对这种能力的提高进行了研究，该提案将进一步确定与外泌体在 RNAi 分子递送中增强功效相关的机制。总的来说，该提案旨在进行深入的临床前研究以及调查外泌体独特的作用机制有可能促进未来对患有以下疾病的患者进行治疗测试 PDAC。