Develop a new cisplatin-based drug combination with reduced ototoxicity

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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.