Exosomes in Cancer Therapy

外泌体在癌症治疗中的应用

• 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
• 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

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)预后差，中位生存期约6个月 适用于转移性疾病患者，尽管使用了目前的治疗方法。因此，迫切需要PDAC 有效的治疗方法。大约80%的PDAC患者表现出KRAS突变，并替换了甘氨酸 第12密码子的残基，如KrasG12D，在高频下观察到。许多对小鼠的研究明确地表明 直接抑制致癌的KRAS显著抑制肿瘤的进展。尽管如此令人信服 致癌KRAS在PDAC发病机制中功能作用的证据，直接靶向致癌 KRAS一直难以捉摸，经常被戏称为“无法下药”。在这项拨款申请中，我们建议 探索一种新的方法来靶向致癌的KRAS，使用被称为外体的生理纳米颗粒。 外体是40-150 nm的胞外小泡(EV)，含有DNA、RNA和蛋白质，可以传递 它们的内容物高效地进入细胞，它们与细胞融合和/或进入。利用外体的这一独特功能，我们的 研究小组在这项拨款申请中提出了一项测试中心假说的建议，该假说认为 设计用于在胰腺癌中靶向KrasG12D的RNA干扰(RNAi)分子。 成功完成拟议的研究将确定外切体是否显示出更好的能力 与脂质体相比，为治疗胰腺癌提供RNAi分子。此外，在此之后 这种增强的能力是使用多个实验系统进行调查的，该提案将进一步确定 机制/S与外切体在递送RNA干扰分子中的增强效率有关。 总的来说，这项建议旨在实现深入的临床前研究，同时调查 Exosome独特的作用机制潜在地促进了未来对慢性粒细胞白血病患者的治疗试验 PDAC。