Exosomes and platinum-induced peripheral neuropathy

外泌体和铂诱导的周围神经病变

• 批准号: 10433899
• 负责人: ZHENG GANG ZHANG
• 金额: $ 35.14万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433899
• 关键词: Acute; Adult; Affect; Afferent Neurons; Animal Model; Axon; Bioinformatics; Blood-Nerve Barrier; Cell Death; Cell Death Signaling Process; Cell Line; Cells; Chemotherapy-induced peripheral neuropathy; Chronic; Cisplatin; Colorectal Cancer; Data; Development; Distal; Dose; Endothelial Cells; Exposure to; Female; Genes; Genomics; Hand; Human; In Vitro; Knock-out; Lead; Lipids; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Messenger RNA; MicroRNAs; Microfluidic Microchips; Molecular; Multidrug Resistance Gene; Mus; Neurons; Neuropathy; Neuroprotective Agents; Ovarian Carcinoma; Parents; Patients; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Platinum; Proteins; Protocols documentation; Quality of life; Reporting; SKOV3 cells; Sensory; Signal Transduction; Source; Spinal Ganglia; Symptoms; Testing; Therapeutic Effect; Treatment Efficacy; Tumor Suppression; Tumor Tissue; Woman; Xenograft procedure; afferent nerve; anti-cancer; axon growth; axonal degeneration; base; brain endothelial cell; cancer cell; cell killing; chemotherapy; clinically relevant; exosome; foot; improved; intercellular communication; multi drug transporter; nanovesicle; neoplastic cell; neuroprotection; neurotoxicity; novel; novel therapeutics; oxaliplatin; patient derived xenograft model; sciatic nerve; sensory neuropathy; tumor; tumor growth; tumor progression

Abstract: Platinum-based drugs are commonly used to treat cancers. Platinum drugs are the first line therapy for ovarian and colorectal cancers. However, chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common complications. More than 70% of the patients receiving oxaliplatin are affected by neuropathy. Oxaliplatin induces two symptoms of peripheral sensory neuropathy; an acute and transient cold-aggravated, and a chronic form that has onset after multiple exposures to the drug and does not disappear with drug cessation. The neurotoxicity often leads to platinum drug dose reductions, compromising efficiency of platinum drugs to suppress tumor progression. On an average of 6 years after chemotherapy, 47% of women still reported symptoms of CIPN. Studies to develop a neuroprotective agent have, to date, been unsuccessful to reduce CIPN. There is an imperative need to develop new therapies to CIPN. Challenges to develop such therapies include that a therapy needs not to impede antitumor efficacy, but to effectively inhibit CIPN. Our preliminary data demonstrated cerebral endothelial cell derived exosomes (CEC-exos) abolish oxaliplatin- induced peripheral neuropathy in tumor bearing mice and sensitize oxaliplatin on cancer cell killing. Exosomes are nanovesicles and mediate intercellular communication by transferring cargo proteins, lipids, and genomic materials including mRNAs and microRNAs (miRNAs) between source and target cells. We found that treatment of the tumor bearing mice with CEC-exos along with oxaliplatin induces a network of miRNAs/mRNAs in sciatic nerves that exerts neuroprotection in sciatic nerves and DRG neurons, but triggers a distinct miRNAs/mRNAs network in tumor to promote cancer cell death. We, thus, hypothesized that CEC- exos mitigate peripheral neurotoxicity induced by platinum drugs and that CEC-exos enhance the anti- cancer efficacy of platinum drugs on tumor cells. Three specific aims are proposed to test this overall hypothesis. Aim 1 is to investigate the efficacy of the CEC-exos on ameliorating platinum drug-induced peripheral neurotoxicity and on improving the treatment of tumor. Aim 2 is to investigate molecular mechanisms underlying the therapeutic effect of CEC-exos on platinum drug-induced peripheral neuropathy with a focus on the interaction between CEC exosomal miRNAs and their target proteins in axons and DRG neurons. Aim 3 is to investigate molecular mechanisms underlying the effect of CEC-exos on sensitizing tumors to platinum drugs with a focus on the interaction between CEC exosomal miRNAs and their target proteins in tumor cells. Accomplishing these aims will potentially lead to development of a new CEC-exo based therapy for CIPN, leading to improvement in the quality of life and possibly cure of cancers.

抽象的： 基于铂的药物通常用于治疗癌症。白金药物是卵巢的第一线治疗 和结直肠癌。但是，化学疗法诱导的周围神经病（CIPN）是最多的。 常见并发症。超过70％的接受奥沙利铂的患者受神经病变的影响。 奥沙利铂诱导周围感觉神经病的两个症状；急性和短暂的冷磨碎， 和一种慢性形式，该慢性形式多次暴露于该药物后发病，并且不会被药物消失 停止。神经毒性通常会导致铂药剂量降低，损害铂的效率 抑制肿瘤进展的药物。化学疗法平均6年，有47％的女性仍在 报道了CIPN的症状。迄今为止，开发神经保护剂的研究还没有成功 减少CIPN。必须开发新的CIPN疗法。发展这样的挑战 疗法包括治疗不需要阻碍抗肿瘤功效，而是有效抑制CIPN。我们的 初步数据表明，脑内皮细胞衍生的外泌体（CEC-EXOS）取消了奥沙利铂 - 在肿瘤轴承小鼠的肿瘤中诱导的周围神经病，并使奥沙利铂对癌细胞杀死敏感。 外泌体是纳米孢子，通过转移货物蛋白，脂质和介导细胞间通信 源和靶细胞之间的基因组材料，包括mRNA和microRNA（miRNA）。我们 发现用CEC-EXOS以及Oxaliptin的治疗肿瘤小鼠诱导了一个网络 在坐骨神经和DRG神经元中施加神经保护的坐骨神经中的miRNA/mRNA，但触发 肿瘤中的一个明显的miRNA/mRNA网络可促进癌细胞死亡。因此，我们假设Cec- EXOS减轻铂药诱导的周围神经毒性，CEC-EXOS增强了抗抗毒性 铂药在肿瘤细胞上的癌症功效。提出了三个特定目标来测试这一总体 假设。 AIM 1是研究CEC-Exos对改善铂药诱导的功效 周围神经毒性和改善肿瘤治疗。目标2是研究分子机制 CEC-EXOS对铂药诱导的周围神经病的治疗作用的基础，重点是 CEC外泌体miRNA与轴突和DRG神经元中其靶蛋白之间的相互作用。 AIM 3是 研究CEC-EXOS对肿瘤敏化铂药的影响的分子机制 侧重于CEC外泌体miRNA与肿瘤细胞中其靶蛋白之间的相互作用。 实现这些目标将有可能导致开发用于CIPN的新的基于CEC-EXO的疗法， 导致生活质量的改善，并可能治愈癌症。

项目成果

Small extracellular vesicles ameliorate peripheral neuropathy and enhance chemotherapy of oxaliplatin on ovarian cancer.

• DOI: 10.1002/jev2.12073
• 发表时间: 2021-03
• 期刊: Journal of extracellular vesicles
• 影响因子: 16
• 作者: Zhang Y;Li C;Qin Y;Cepparulo P;Millman M;Chopp M;Kemper A;Szalad A;Lu X;Wang L;Zhang ZG
• 通讯作者: Zhang ZG