Therapeutics to prevent cisplatin-induced hearing loss by transcriptomics

Therapeutics to prevent cisplatin-induced hearing loss by transcriptomics PROJECT SUMMARYCisplatin is one of the most effective platinum-based compounds in the treatment of various types of malignancies, including head and neck, ovarian, and lung cancer. Despite its efficacy, ototoxcity, neurotoxicity, and nephrotoxicity stand out as the top three dose-limiting side effects of cisplatin chemotherapy.Ototoxicity refers to drug or chemical-related damage to the inner ear sensory cells and neurons, resulting in permanent, irreversible hearing loss. Elevation of hearing thresholds have been reported in the majority of patients treated with cisplatin. To date, there are no FDA-approved drugs for the treatment of cisplatin-induced hearing loss.This study aims to prevent cisplatin-induced damage to the inner ear cells by investigating drug candidates which activate multiple pathways involved in mechanisms of cisplatin resistance. Using recent advances in developing bioinformatic web-based tools that integrate genomic portraits and compound activities, we have identified 6 FDA-approved candidate drugs that could be associated with a cisplatin-resistant phenotype. The 6 final top drugs were selected based on their FDA-approval and ability to grant at least 40% protection in either cellular or zebrafish models. The drug providing the highest protection in cell culture, zebrafish and cochlear explant models has also been shown to have synergistic effects on cisplatin in cancer cells and can cross the blood-brain-barrier. Therefore, the combination of its protective nature in cochlear cells and destructive nature in cancer cells makes it a viable option as a drug for cisplatin resistance for the inner ear.The results of this study will provide the key proof of principle to develop novel therapeutic strategies against side effects of cisplatin chemotherapy. Moreover, our studies will provide mechanisms of action of cisplatin-induced hearing loss. Repurposing this FDA-approved drug for new function against the side-effects of cisplatin chemotherapy will significantly expedite the FDA approval process and reduce its cost.PROJECT NARRATIVE The work in this proposal focuses on repurposing an FDA approved drug for preventing cisplatin-induced hearing loss. If successful, this project will be a significant step forward in the treatment of cisplatin-induced hearing loss in cancer patients.