Therapeutics to prevent cisplatin-induced hearing loss by transcriptomics

通过转录组学预防顺铂诱导的听力损失的治疗药物 项目摘要 顺铂是治疗各种类型的最有效的铂类化合物之一 恶性肿瘤，包括头颈癌、卵巢癌和肺癌。尽管它的功效，耳毒性， 神经毒性和肾毒性是顺铂的三大剂量限制性副作用 化疗 耳毒性是指药物或化学物质对内耳感觉细胞和神经元的损伤， 导致永久性的不可逆的听力损失。据报道，听力阈值升高 在大多数接受顺铂治疗的患者中。迄今为止，没有FDA批准的药物用于 治疗顺铂引起的听力损失。 本研究的目的是通过研究药物预防顺铂对内耳细胞的损伤， 激活参与顺铂耐药机制的多种途径的候选物。使用 在开发基于网络的生物信息学工具方面的最新进展， 化合物活性，我们已经确定了6种FDA批准的候选药物， 具有顺铂耐药表型最终的6种顶级药物是根据其FDA批准而选择的 以及在细胞或斑马鱼模型中给予至少40%保护的能力。药物提供 在细胞培养、斑马鱼和耳蜗外植体模型中的最高保护也已被证明， 对癌细胞中的顺铂具有协同作用，并且可以穿过血脑屏障。因此，我们认为， 其在耳蜗细胞中的保护性质和在癌细胞中的破坏性质的组合使得 它是治疗内耳顺铂耐药性的一个可行的选择。 本研究的结果将为开发新的治疗方法提供关键的原理依据。 顺铂化疗副作用的防治策略。此外，我们的研究将提供 顺铂引起的听力损失的作用机制。将这种FDA批准的药物重新用于新的 对顺铂化疗的副作用的作用将大大加快FDA的批准 加工，降低成本。

Therapeutics to prevent cisplatin-induced hearing loss by transcriptomics PROJECT SUMMARY Cisplatin 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.