Develop a new cisplatin-based drug combination with reduced ototoxicity

开发一种新的顺铂药物组合，降低耳毒性

• 批准号: 9408928
• 负责人: Jianxin Bao
• 金额: $ 22.47万
• 依托单位: GATEWAY BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9408928
• 关键词: A549; Address; Adverse effects; Analysis of Variance; Antineoplastic Agents; Antioxidants; Auditory Brainstem Responses; Bilateral; Biological Assay; Biological Preservation; Bromides; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Death; Cells; Cessation of life; Cisplatin; Clinical Research; Cochlea; Computer software; Data; Disease; Dose; Drug Combinations; Epidermal Growth Factor Receptor; Equation; Exhibits; Flunarizine; Future; Goals; In Vitro; Injection of therapeutic agent; Investigational Drugs; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Mutation; Noise-Induced Hearing Loss; Non-Small-Cell Lung Carcinoma; Organ; Outcome; Outer Hair Cells; Pharmaceutical Preparations; Pharmacotherapy; Platinum; Production; Property; Rattus; Reactive Oxygen Species; Saline; Signal Pathway; Solid; Solid Neoplasm; T-Type Calcium Channels; Testing; Tetrazolium; Therapeutic Effect; Time; base; cancer cell; cancer therapy; cytotoxic; cytotoxicity; design; dosage; drug development; hearing impairment; in vivo; indexing; intraperitoneal; killings; novel anticancer drug; novel drug combination; novel therapeutics; otoacoustic emission; ototoxicity; oxaliplatin; prevent; public health relevance; synergism; treatment group; tumor

PROJECT SUMMARY In spite of recent new drug developments, platinum-based drugs such as cisplatin are still widely used to treat solid organ malignancies. Besides its limited efficacy, serious side effects have been associated with the use of cisplatin, such as bilateral and irreversible hearing loss. In the cochlea, cisplatin can trigger the production of reactive oxygen species, and activate several other signaling pathways. A variety of agents, mainly based on their antioxidant properties, have been tested against cisplatin-induced ototoxicity. However, many of them show limited efficacies, and also interfere with the therapeutic effect of cisplatin. Extensive in vitro studies have indicated that flunarizine (Sibelium), a drug that blocks T-type calcium channels, can protect cochlear cells against cisplatin-induced cytotoxicity. This drug also has strong anti-tumor activities that act synergistically on several important aspects of cancer treatment. Our preliminary studies have found that flunarizine can synergistically induce cell death with cisplatin in one lung cancer cell line, and it can also protect noise-induced hearing loss. Based on these findings, we propose to develop a new cancer drug combination by testing whether flunarizine can synergistically induce cancer cell death with cisplatin, and at the same time, prevent cisplatin-induced ototoxicity. Because lung cancer is the leading cause of cancer-related death globally, and cisplatin is widely used to treat this disease, here, we will first determine the cytotoxic effects of flunarizine and cisplatin in two lung cancer cell lines: A549 and H1975, and determine whether flunarizine and cisplatin have synergistic effects in these cancer cells when used in combination (Aim 1). We will then determine whether flunarizine can prevent cisplatin- induced ototoxicity in vivo (Aim 2). In short, based on previous studies and our preliminary data, our project goal is to repurpose flunarizine to combine with cisplatin against solid tumors with a focus on lung cancer. This project will generate data important to complete an Investigational New Drug (IND)-enabling data package for future clinical studies. The ultimate goal is to develop an effective cancer drug combination with fewer side effects.

项目概要 尽管最近有新药开发，但顺铂等铂类药物仍然 广泛用于治疗实体器官恶性肿瘤。除了疗效有限外，还有严重的副作用 与顺铂的使用有关，例如双侧和不可逆的听力损失。在 顺铂可以触发耳蜗产生活性氧，并激活其他几种 信号通路。主要基于其抗氧化特性，已开发出多种抗氧化剂。 针对顺铂引起的耳毒性进行了测试。然而，其中许多药物的功效有限，而且 干扰顺铂的治疗效果。广泛的体外研究表明 氟桂利嗪（Sibelium）是一种阻断 T 型钙通道的药物，可以保护耳蜗细胞免受 顺铂诱导的细胞毒性。该药物还具有很强的抗肿瘤活性，可协同作用 癌症治疗的几个重要方面。我们的初步研究发现氟桂利嗪 在一种肺癌细胞系中可以与顺铂协同诱导细胞死亡，并且还可以保护 噪音引起的听力损失。基于这些发现，我们建议开发一种新的抗癌药物 通过测试氟桂利嗪是否可以与顺铂协同诱导癌细胞死亡， 同时，预防顺铂引起的耳毒性。因为肺癌是主要原因 全球癌症相关死亡的比例很高，顺铂被广泛用于治疗这种疾病，在这里，我们首先 确定氟桂利嗪和顺铂对两种肺癌细胞系：A549 和 H1975，并确定氟桂利嗪和顺铂在这些癌细胞中是否具有协同作用 组合使用时（目标 1）。然后我们将确定氟桂利嗪是否可以预防顺铂- 诱导体内耳毒性（目标 2）。 简而言之，根据之前的研究和我们的初步数据，我们的项目目标是重新利用 氟桂利嗪与顺铂联合治疗实体瘤，重点是肺癌。该项目将 生成对于完成新药研究 (IND) 支持数据包很重要的数据 未来的临床研究。最终目标是开发一种有效的抗癌药物组合，且用量更少 副作用。