Develop a new cisplatin-based drug combination with reduced ototoxicity

项目总结 尽管最近有新的药物开发，但以铂为基础的药物，如顺铂，仍然 广泛用于治疗实体器官恶性肿瘤。除了疗效有限，严重的副作用还有 与顺铂的使用有关，如双侧和不可逆性听力损失。在 在耳蜗组织中，顺铂可以触发活性氧的产生，并激活其他几种 信号通路。各种各样的试剂，主要是基于它们的抗氧化性能，已经被 经测试可对抗顺铂引起的耳毒性。然而，它们中的许多显示出有限的有效性，而且 干扰顺铂的治疗效果。广泛的体外研究表明， 氟桂利嗪(西比灵)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。这种药物还具有很强的抗肿瘤活性，可以协同作用于 癌症治疗的几个重要方面。我们的初步研究发现氟桂利嗪 能协同顺铂诱导一株肺癌细胞死亡，并具有保护作用 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 通过检测氟桂利嗪是否与顺铂协同诱导癌细胞死亡， 同时预防顺铂所致耳毒性。因为肺癌是最主要的原因 而顺铂被广泛用于治疗这种疾病，在这里，我们首先 测定氟桂利嗪和顺铂对两种肺癌细胞株A549和A549的细胞毒作用 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 当组合使用时(目标1)。然后我们将确定氟桂利嗪是否可以预防顺铂- 体内诱发耳毒性(AIM 2)。 简而言之，基于之前的研究和我们的初步数据，我们的项目目标是重新调整用途 氟桂利嗪联合顺铂治疗实体瘤，重点是肺癌。这个项目将 为完成研究新药(IND)启用数据包生成重要数据 未来的临床研究。最终的目标是开发一种有效的抗癌药物组合，用更少的 副作用。

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.