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）的预后较差，中位存活率约为6个月对于转移性疾病目的地的患者，目前治疗的使用。因此，PDAC迫切需要有效的疗法。大约80％的PDAC患者在KRAS中表现出突变，取代了甘氨酸高频观察到的密码子12（例如KRASG12D）的住所。在小鼠中的许多研究明确表明直接抑制致癌性KRA可显着抑制肿瘤的进展。尽管如此引人注目致癌kras在PDAC发病机理中的功能作用的证据，直接靶向致癌克拉斯（Kras）难以捉摸，它通常被称为“不难的”。在此赠款申请中，我们建议使用称为外泌体的物理纳米颗粒探索一种新的方法来靶向致癌性KRA。外泌体是包含DNA，RNA和蛋白质的40-150 nm细胞外蔬菜（EV），可以递送它们的内容有效地与单元格融合和/或输入。利用外泌体的这一独特功能，我们的研究团队在此赠款申请中提出的建议，以检验“外部可以是设计为递送RNA干扰（RNAI）分子以靶向胰腺癌的Krasg12d。成功完成拟议的研究将确定外泌体是否表现出较高的能力与脂质体相比，递送RNAi分子用于治疗胰腺癌。此外，之后使用多个实验系统研究了这种提高能力，该提案将进一步确定机制与外泌体在RNAi分子递送中的效率提高相关。该提案旨在实现深入的临床前研究，并研究外泌体的独特作用机理在潜在地支持未来的治疗测试的患者中 PDAC。