Exosomes and platinum-induced peripheral neuropathy

外泌体和铂诱导的周围神经病变

基本信息

批准号：
10199955
负责人：
ZHENG GANG ZHANG
金额：
$ 35.85万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199955
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

项目摘要

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：铂类药物通常用于治疗癌症。铂类药物是卵巢癌的一线治疗药物和结直肠癌。然而，化疗引起的周围神经病变（CIPN）是最常见的疾病之一。常见并发症。超过 70% 接受奥沙利铂治疗的患者患有神经病变。奥沙利铂会诱发周围感觉神经病的两种症状；急性且短暂的寒冷加重，慢性形式在多次接触药物后发病，并且不会随药物消失停止。神经毒性常常导致铂类药物剂量减少，从而损害铂类药物的效率抑制肿瘤进展的药物。化疗后平均 6 年，47% 的女性仍然报告了 CIPN 的症状。迄今为止，开发神经保护剂的研究尚未成功减少 CIPN。迫切需要开发新的 CIPN 疗法。开发此类产品面临的挑战治疗包括治疗不需要妨碍抗肿瘤功效，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）消除了奥沙利铂- 诱导荷瘤小鼠周围神经病变，并使奥沙利铂对癌细胞杀伤敏感。外泌体是纳米囊泡，通过转移货物蛋白、脂质和物质来介导细胞间通讯基因组材料，包括源细胞和靶细胞之间的 mRNA 和 microRNA (miRNA)。我们发现用 CEC-exos 和奥沙利铂治疗荷瘤小鼠会诱导一个网络坐骨神经中的 miRNA/mRNA 对坐骨神经和 DRG 神经元发挥神经保护作用，但会触发肿瘤中独特的 miRNA/mRNA 网络可促进癌细胞死亡。因此，我们假设 CEC- exos 减轻铂类药物引起的周围神经毒性，CEC-exos 增强抗- 铂类药物对肿瘤细胞的癌症功效。提出了三个具体目标来测试总体情况假设。目的 1 是研究 CEC-exos 对改善铂类药物诱导的周围神经毒性和改善肿瘤的治疗。目标2是研究分子机制 CEC-exos 对铂类药物引起的周围神经病变的治疗作用的基础，重点是 CEC 外泌体 miRNA 与其在轴突和 DRG 神经元中的靶蛋白之间的相互作用。目标 3 是研究 CEC-exos 使肿瘤对铂类药物敏感的分子机制重点关注 CEC 外泌体 miRNA 与其在肿瘤细胞中的靶蛋白之间的相互作用。实现这些目标将有可能开发出一种新的基于 CEC-exo 的 CIPN 疗法，从而改善生活质量并可能治愈癌症。