Therapeutics to prevent cisplatin-induced hearing loss by transcriptomics

通过转录组学预防顺铂引起的听力损失的治疗

基本信息

批准号：
10007294
负责人：
Pezhman Salehi Dermanaki
金额：
$ 20.57万
依托单位：
TING THERAPEUTICS LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2021-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10007294
关键词：
Animal Model Auditory Brainstem Responses Auditory Threshold Bioinformatics Blood - brain barrier anatomy Cancer Patient Cell Culture Techniques Cell Line Cells Cisplatin Cochlea Databases Dose Dose-Limiting Drug or Chemical FVB Mouse Freedom Genomics Goals Grant Hair Cells Head Cancer In Vitro Injections Intraperitoneal Injections Investigational Therapies Labyrinth Legal patent Licensing Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Maps Modeling Morphology Mus Nature Neck Cancer Neurons Organ of Corti Orphan Drugs Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Platinum Portraits Principal Investigator Process Publishing Reporting Resistance Sensory Stria Vascularis Testing Therapeutic Time United States Food and Drug Administration Universities Work Zebrafish auditory threshold shift base cancer cell cancer therapy chemotherapy cisplatin induced hearing loss cost cytotoxicity drug candidate hearing impairment in vivo in vivo Model intraperitoneal lateral line mouse model nephrotoxicity neuromast neurotoxicity novel novel therapeutics otoprotectant ototoxicity permanent hearing loss pre-clinical prevent prevent hearing loss side effect spiral ganglion transcriptome transcriptome sequencing transcriptomics web-based tool

项目摘要

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.

通过转录组学预防顺铂引起的听力损失的治疗项目概要顺铂是治疗各种类型最有效的铂基化合物之一恶性肿瘤，包括头颈癌、卵巢癌和肺癌。尽管它有功效，但有耳毒性，神经毒性和肾毒性是顺铂的三大剂量限制性副作用化疗。耳毒性是指与药物或化学物质相关的对内耳感觉细胞和神经元的损害，导致永久性、不可逆转的听力损失。据报道听力阈值升高大多数接受顺铂治疗的患者。迄今为止，尚无 FDA 批准的药物治疗顺铂引起的听力损失。本研究旨在通过研究药物来预防顺铂引起的内耳细胞损伤激活涉及顺铂耐药机制的多种途径的候选者。使用开发基于网络的生物信息学工具的最新进展，该工具集成了基因组肖像和化合物活性，我们已经确定了 6 种 FDA 批准的可能相关的候选药物具有顺铂耐药表型。根据 FDA 批准情况选出最终的 6 种顶级药物并能够在细胞或斑马鱼模型中提供至少 40% 的保护。提供药物细胞培养、斑马鱼和耳蜗外植体模型中的最高保护也被证明与癌细胞中的顺铂有协同作用，并能穿过血脑屏障。所以，它对耳蜗细胞的保护性质和对癌细胞的破坏性质的结合使得作为治疗内耳顺铂耐药性的药物，它是一个可行的选择。这项研究的结果将为开发新的治疗方法提供关键的原理证明针对顺铂化疗副作用的策略。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药物对抗顺铂化疗副作用的功能将显着加快 FDA 批准处理并降低其成本。