Aerosol Delivery of Topotecan for Personalized Lung Cancer Therapy

拓扑替康气雾剂递送用于个体化肺癌治疗

基本信息

批准号：
9029727
负责人：
Philip Kuehl
金额：
$ 50.62万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
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：
2016-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029727
关键词：
Accounting Aerosols Antineoplastic Agents Biological Assay Biological Markers Biomedical Engineering Blood Circulation Breathing Camptothecin Camptothecin Analogue Cancer Etiology Cancer Model Cancer Patient Cancer cell line Cell Line Cells Characteristics Clinic Clinical Clinical Trials Complement Data Deposition Diagnosis Distant Dose Drug Delivery Systems Drug Kinetics Engraftment Enzymes Epidermal Growth Factor Receptor Epigenetic Process Erlotinib Excision FDA approved Formulation Gefitinib Gene Expression Genes Genetic Heterogeneity Goals Growth Hepatic Human In Vitro Intravenous Intravenous infusion procedures Intubation Laboratory Rat Lead Lung Lung Neoplasms Malignant neoplasm of lung Methylation MicroRNAs Monitor Mutation Non-Small-Cell Lung Carcinoma Nude Mice Nude Rats Patients Pharmaceutical Preparations Plasma Powder dose form Prodrugs Progression-Free Survivals Property Rattus Resistance Staging System Testing Tissues Topoisomerase-I Inhibitor Topotecan Toxic effect Treatment Efficacy Tumor Burden Tumor Suppression Xenograft procedure aerosolized air filter aqueous base cancer cell cancer survival cancer therapy cancer type chemotherapy comparative efficacy genome-wide genome-wide analysis improved in vivo innovation molecular marker mortality novel novel marker outcome forecast personalized medicine precision medicine predicting response promoter public health relevance response subcutaneous systemic toxicity treatment response tumor tumor growth tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): The prognosis of patients receiving chemotherapy for advanced non-small cell lung cancer (NSCLC) remains very poor. Emerging evidence indicates that the response rate of NSCLC patients to currently used anticancer drugs could be increased by preselecting the most responsive patients for personalized therapy. This requires molecular biomarkers indicative of sensitivity to the specific drug. We have recently identified that high ISG15 expression indicates sensitivity of lung cancer cells to topotecan (TPT). Intravenous (IV) infusion of TPT is FDA approved for lung cancer but its use is limited due to a severe hematological toxicity in some patients. This application aims to improve the efficacy and toxicity of TPT through three innovative approaches: 1) A bioengineering concept driven strategy to manufacture and deliver a spray-dried powder of TPT via inhalation, which allows effective drug concentration in the lungs while reducing it in the systemic circulation. 2) A novel biomarker for preselecting the most TPT-sensitive NSCLC cells. 3) The use of a unique orthotropic lung cancer model in which human NSCLC cells are engrafted throughout the lungs of the nude rat, a semi- natural system that captures the impact of the tumor-microenvironment on tumor growth and treatment response. Studies under Aim-1 will produce a spray-dried powder formulation of TPT, evaluate its aerosol property, and characterize its plasma and pulmonary pharmacokinetics with respect to the standard IV TPT delivery in the nude rat. Under Aim-2 human NSCLC cell lines that are preselected for TPT-sensitivity (n=2) or resistance (n=2) based on ISG15 expression will be instilled into the lungs of nude rats via tracheal intubation. After 3 weeks of tumor growth, the rats will be treated once-a-week for 4 weeks with vehicle (filtered air), 3 different doses of inhaled-TPT, or an IV-TPT, and the toxicity and efficacy to suppress tumor growth will be determined. Aim-3 will use nude rats engrafted with the 2 most TPT-sensitive cell lines to compare the impact of vehicle, inhaled-TPT, and IV TPT therapy in improving lung cancer survival. Additional studies under this aim will use subcutaneous xenografts of the two TPT-sensitive cell lines to evaluate the impact of these treatments in suppressing extrapulmonary growth of lung cancer. Finally, studies under Aim-4 will determine TPT-sensitivity of 36 NSCLC cell lines in vitro, and screen the genome-wide gene and microRNA expression of TPT-sensitive and resistant cell lines (n=10 each). The goal is to identify additional biomarkers that could discriminate NSCLC cells by TPT-sensitivity. The potential of the top biomarkers to complement and improve the ISG15-based preselection of lung cancer patients that are most responsive to TPT therapy will be determined using lung tumor-normal pairs from 100 NSCLC patient. These studies have the potential to significantly improve the efficacy and utility of this potent anticancer drug and due to its approval and availability in the clinic could immediately impact NSCLC therapy.

描述（申请人提供）：接受化疗的晚期非小细胞肺癌（NSCLC）患者的预后仍然很差。新出现的证据表明，通过预先选择最有效的抗癌药物可以提高 NSCLC 患者对当前使用的抗癌药物的反应率。这需要指示对特定药物敏感的分子生物标志物，我们最近发现高 ISG15 表达表明肺癌细胞对拓扑替康 (TPT) 敏感。静脉（IV）输注 TPT 已被 FDA 批准用于肺癌，但由于某些患者存在严重的血液学毒性，其使用受到限制。该应用旨在提高疗效和毒性。 TPT 通过三种创新方法进行：1) 生物工程概念驱动的策略，通过吸入制造和输送 TPT 喷雾干燥粉末，从而使药物在肺部有效浓度，同时减少全身循环中的药物浓度；2) 一种新颖的生物标志物。 3) 使用独特的正交向性肺癌模型，将人类 NSCLC 细胞移植到裸鼠的整个肺部，这是一种半自然系统， Aim-1 下的研究将捕捉肿瘤微环境对肿瘤生长和治疗反应的影响，生产 TPT 喷雾干燥粉末制剂，评估其气雾剂特性，并根据标准 IV TPT 表征其血浆和肺部药代动力学。在 Aim-2 下，根据 ISG15 表达预先选择 TPT 敏感性 (n=2) 或耐药性 (n=2) 的人类 NSCLC 细胞系将被注入大鼠体内。肿瘤生长 3 周后，每周一次用载体（过滤空气）、3 种不同剂量的吸入 TPT 或 IV-TPT 治疗大鼠，持续 4 周。 Aim-3 将使用移植了两种对 TPT 最敏感的细胞系的裸鼠来确定载体、吸入 TPT 和静脉注射 TPT 的影响。该目标下的其他研究将使用两种 TPT 敏感细胞系的皮下异种移植物来评估这些治疗在抑制肺癌肺外生长方面的影响。最后，Aim-4 下的研究将确定 TPT-。体外检测 36 种 NSCLC 细胞系的敏感性，并筛选 TPT 敏感和耐药细胞系（各 n=10）的全基因组基因和 microRNA 表达。 NSCLC 细胞的 TPT 敏感性将使用来自 100 名 NSCLC 患者的肺肿瘤-正常配对来确定顶级生物标志物补充和改善对 TPT 治疗最敏感的基于 ISG15 的预选的潜力。这种强效抗癌药物的疗效和实用性有显着提高的潜力，并且由于其在临床上的批准和可用性，可能会立即影响非小细胞肺癌的治疗。