Role of MCT6 in mediating cisplatin-induced ototoxicity

摘要 顺铂是最广泛使用的抗癌药物之一，然而高达70%的患者可能患有严重的肿瘤。 剂量限制性耳毒性。铂介导的听力损失对儿童的早期言语发育不利。 儿童，并可能阻碍神经认知能力，社会融合和财务状况。因此，长期以来- 与此建议相关的一个长期目标是评估膜转运蛋白在调节损伤中的作用 顺铂或其代谢物蓄积后的耳蜗细胞。本提案的总体目标是 描述单羧酸转运蛋白MCT 6在介导顺铂诱导的听力中的作用 损失中心假设是MCT 6促进摄取的N-乙酰半胱氨酸S-共轭代谢物 顺铂（NAC-1）导致耳蜗毛细胞严重损伤和听力丧失。这样做的理由 一个预测的功能降低的MCT 6遗传变异体（rs 4788863）先前与 顺铂诱导的耳毒性发生率较低。评价MCT 6促进 顺铂介导的听力损失是必要的，以解决是否药物抑制这种转运蛋白 将保护当前没有治疗或预防措施的不良事件。中央 将通过追求两个具体目标来检验假设：1）研究MCT 6转运NAC-1的能力; （2）在体内测定MCT 6缺陷对顺铂诱导的耳毒性的保护作用。根据第一项 目的是，将使用高表达MCT 6的体外模型来测量这种转运蛋白的能力， 调节NAC-1以及顺铂的摄取。此外，rs 478863遗传变异或 将评估MCT 6对铂摄取的药理学抑制或细胞毒性。在第二个目标下， 将使用MCT 6缺陷的体内小鼠模型来评价顺铂诱导的听力损失的严重性， MCT 6转运蛋白的缺失此外，我们将测量MCT 6中顺铂的药代动力学变化。 缺陷小鼠这将提供对MCT 6在处理顺铂或其代谢产物中的作用的机制性见解。 代谢物。本申请中提出的研究是创新的，因为它代表了一种实质性的 通过评估MCT 6作为耳蜗损伤调节剂的作用， 毒性顺铂代谢物的积累。这项研究意义重大，因为它有望 将MCT 6鉴定为可以靶向治疗以降低或预防， 与癌症治疗相关的顺铂引起的听力损失。最终，这些知识预计将减少 将经历重大社会和经济挑战的患者人数，包括年轻人 儿科癌症幸存者

ABSTRACT Cisplatin is one of the most widely used anti-cancer drugs, however up to 70% of patients can suffer from severe dose-limiting ototoxicity. Platinum-mediated hearing loss is detrimental to the early speech development of children and can impede neurocognitive abilities, social integration, and financial status. Therefore, the long- term goal associated with this proposal is to assess the role of membrane transporters in regulating damage to cochlear cells following accumulation of cisplatin or its metabolites. The overall objective of this proposal is to delineate the involvement of the monocarboxylate transporter, MCT6, in mediating cisplatin-induced hearing loss. The central hypothesis is that MCT6 promotes uptake of an N-acetylcysteine S-conjugate metabolite of cisplatin (NAC-1) resulting in severe damage to cochlear hair cells and loss of hearing. The rationale for this project is that a predicted reduced functional genetic variant of MCT6 (rs4788863) was previously associated with lower rates of cisplatin-induced ototoxicity. Evaluating the mechanism by which MCT6 contributes to cisplatin-mediated hearing loss is necessary to address whether pharmacological inhibition of this transporter would be protective of an adverse event that has no current curative or preventative measures. The central hypothesis will be tested by pursuing two specific aims: 1) Investigate the ability of MCT6 to transport NAC-1; and 2) Determine the protective effect of MCT6-deficiency on cisplatin-induced ototoxicity in vivo. Under the first aim, in vitro models with high expression of MCT6 will be used to measure the ability of this transporter to modulate uptake of NAC-1 as well as cisplatin. Additionally, the influence of the rs478863 genetic variant, or pharmacological inhibition of MCT6, on platinum uptake or cytotoxicity will be assessed. Under the second aim, a MCT6-deficient in vivo mouse model will be used to evaluate the severity of cisplatin-induced hearing loss in the absence of the MCT6 transporter. Moreover, we will measure pharmacokinetic changes of cisplatin in MCT6- deficient mice. This will provide mechanistic insight into the role of MCT6 in the handling of cisplatin or its metabolites. The research proposed in this application is innovative because it represents a substantive departure from the status quo by evaluating the role MCT6 as a regulator of cochlear damage via facilitating accumulation of a toxic cisplatin metabolite. The proposed research is significant because it is expected to identify MCT6 as a transporter that can be pharmacologically targeted to reduce the severity of, or prevent, cisplatin-induced hearing loss associated with cancer therapy. Ultimately, such knowledge is predicted to reduce the number of patients who would experience significant social and economic challenges, including in young pediatric cancer survivors.