Novel approach to attenuate small cell lung cancer growth and metastasis

减弱小细胞肺癌生长和转移的新方法

• 批准号: 9604665
• 负责人: Mohd Wasim Nasser
• 金额: $ 53.22万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9604665
• 关键词: AMD3100; Apoptosis; Attenuated; Biological Markers; Biological Models; CXCL12 gene; CXCR4 gene; Cancer Patient; Cancer cell line; Cause of Death; Cell Line; Cells; Characteristics; Cisplatin; Clinical; Data; Detection; Development; Disease; Disseminated Malignant Neoplasm; Down-Regulation; Drug resistance; Early Diagnosis; Fibroblasts; Formulation; Gene Expression; Gene Silencing; Genetic Transcription; Goals; Growth; Human; Human Characteristics; Infection; Knowledge; Malignant Neoplasms; Malignant neoplasm of lung; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Liver; MicroRNAs; Mus; Nanotechnology; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nose; Pathway interactions; Patients; Platinum; Play; Polymers; Population; Preclinical Testing; Primary carcinoma of the liver cells; Recurrence; Regulation; Relapse; Research; Resistance; Role; Sampling; Series; Serum; Signal Transduction; Specimen; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Time; Tissue Microarray; Transgenic Organisms; Treatment Efficacy; Tumor Cell Line; Tumor Tissue; Up-Regulation; advanced disease; angiogenesis; base; cancer diagnosis; cancer drug resistance; cancer therapy; chemosensitizing agent; clinically relevant; design; drug development; early detection biomarkers; innovation; insight; lung small cell carcinoma; miRNA expression profiling; migration; mouse model; nanocarrier; nanoformulation; nanoparticle; nanoparticle delivery; neurotensin mimic 1; new therapeutic target; novel; novel marker; novel strategies; novel therapeutics; outcome forecast; pre-clinical; response; targeted treatment; transcriptome; transcriptome sequencing; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression

Abstract Small cell lung cancer (SCLC) is highly aggressive and metastatic malignancy. Unfortunately, no single targeted therapy has shown clinical activity in SCLC and its 5-year survival rate is only 6-8%. Therefore, there is an urgent need to develop innovative strategies against SCLC. In recent years, microRNAs (miRs) have been shown to play significant roles in cancer at the post-translational/transcriptional level by silencing gene expression. Our preliminary data showed reduced expression of miR-1 in SCLC cell lines as well as patient samples. We also observed that miR-1 is inversely associated with CXCR4 in SCLC cell lines and in patient samples. CXCR4/CXCL12-signaling axis has been explored as a major metastatic signaling axis for various cancers including lung cancer. However, not much is known about the role of miR-1 in regulating CXCR4 in SCLC. Our central hypothesis, based on our preliminary data, is that downregulation of miR-1 contributes to SCLC growth and metastasis by upregulating CXCR4. In this application, we propose to develop nanoformulation platform for dual-targeting polymeric CXCR4 antagonist (PCX) nanoparticles (NPs) containing miR-1 mimics for targeting SCLC. We will pursue three specific aims to test our hypothesis. Aim 1 will focus to establish functional miR-1 and CXCR4 axis in SCLC using cell lines and patient samples. These studies will help us to define the novel role of miR-1 downregulation and CXCR4 upregulation for the early detection of SCLC. Additionally, we will perform global transcriptome (miRNA-Seq/RNA-Seq) integrative analysis to explore novel miRs and their targets in SCLC. Aim 2 will be focused on optimization and characterization of PCX-miR-1NPs in SCLC. Since SCLC is highly aggressive and metastatic, we will evaluate whether PCX-miR-1 NPs simultaneously restore miR-1, block the CXCL12/CXCR4 axis, and thereby inhibit metastasis of SCLC in preclinical mouse models. Aim 3 will be designed to analyze therapeutic efficacy of PCX- miR-1NPs in SCLC spontaneous RP (Rbf/f; Tp53f/f; Rosa) mouse model. Upon nasal infection of Ad-cre, RP mice develop tumors that recapitulate human SCLC characteristics. These tumors are highly aggressive and metastatic, and therefore, PCX-miR-1 NPs will serve as ideal nanoformulation-based therapy for the management of SCLC. In addition, cisplatin treatment has been shown to enhance drug resistance through increase CD133+/CXCR4+ cell populations in lung cancer. In this aim, we will also analyze if PCX-miR-1 NPs enhance cisplatin sensitization by reprogramming cancer-associated fibroblasts. Additionally, we will identify novel targets of miR-1 for SCLC using global transcriptome analysis of PCX-miR-1 and cisplatin treated tumor samples. Altogether, the proposed studies will establish the clinical utility of PCX-miR-1 NPs as a novel therapeutic strategy for the treatment of SCLC patients who are difficult to treat due to their advanced disease stage and/or development of drug resistance and recurrence. Nanotechnogy formulation generated in this project will also have broader application in other aggressive and metastatic cancers that have low miR-1 and high CXCR4 expression.

抽象的 小细胞肺癌（SCLC）是一种高度侵袭性和转移性恶性肿瘤。不幸的是，没有一个 靶向治疗在SCLC中已显示出临床活性，其5年生存率仅为6-8%。因此，有 迫切需要制定针对 SCLC 的创新策略。近年来，微小RNA（miR） 已被证明通过沉默基因在翻译后/转录水平上在癌症中发挥重要作用 表达。我们的初步数据显示 SCLC 细胞系以及患者中 miR-1 的表达降低 样品。我们还观察到，在 SCLC 细胞系和患者中，miR-1 与 CXCR4 呈负相关。 样品。 CXCR4/CXCL12信号轴已被探索作为多种癌症的主要转移信号轴 癌症，包括肺癌。然而，对于 miR-1 在调节 CXCR4 中的作用知之甚少。 小细胞肺癌。根据我们的初步数据，我们的中心假设是 miR-1 的下调 通过上调 CXCR4 促进 SCLC 生长和转移。在本申请中，我们建议 开发双靶向聚合CXCR4拮抗剂（PCX）纳米颗粒（NP）的纳米制剂平台 含有用于靶向 SCLC 的 miR-1 模拟物。我们将追求三个具体目标来检验我们的假设。目标1将 重点使用细胞系和患者样本在 SCLC 中建立功能性 miR-1 和 CXCR4 轴。这些 研究将帮助我们确定 miR-1 下调和 CXCR4 上调在早期的新作用 SCLC 的检测。此外，我们还将进行全局转录组（miRNA-Seq/RNA-Seq）整合 分析探索 SCLC 中的新 miR 及其靶点。目标 2 将侧重于优化和 SCLC 中 PCX-miR-1NP 的表征。由于 SCLC 具有高度侵袭性和转移性，我们将评估 PCX-miR-1 NPs是否同时恢复miR-1，阻断CXCL12/CXCR4轴，从而抑制 临床前小鼠模型中 SCLC 的转移。目标 3 将旨在分析 PCX-的治疗效果 SCLC 自发 RP（Rbf/f；Tp53f/f；Rosa）小鼠模型中的 miR-1NP。 Ad-cre、RP 小鼠鼻腔感染后 开发重现人类 SCLC 特征的肿瘤。这些肿瘤具有高度侵袭性 因此，PCX-miR-1 NP 将作为理想的基于纳米制剂的治疗方法 小细胞肺癌。此外，顺铂治疗已被证明可以通过增加耐药性来增强耐药性。 肺癌中的 CD133+/CXCR4+ 细胞群。为此，我们还将分析 PCX-miR-1 NPs 是否增强 通过重新编程癌症相关成纤维细胞来实现顺铂敏化。此外，我们将确定新的目标 使用 PCX-miR-1 和顺铂治疗的肿瘤样本的全局转录组分析，对 miR-1 进行 SCLC 分析。 总而言之，拟议的研究将确立 PCX-miR-1 NP 作为一种新型治疗策略的临床效用 用于治疗因晚期疾病阶段和/或而难以治疗的 SCLC 患者 耐药性的发展和复发。该项目中产生的纳米技术配方还将具有 更广泛地应用于其他具有低 miR-1 和高 CXCR4 表达的侵袭性和转移性癌症。