Grant: Project Grant

Cisplatin is the chemotherapy of choice for the treatment of solid tumours in children; however, about half of these children experience some form of hearing loss that is caused by this drug. Hearing loss in children is especially detrimental because this is a critical time when learning and socialization skills are developed. Negative impacts have also been documented into adulthood. The goal of this project is to take advantage of the link between cisplatin hearing damage and a cell surface receptor that is normally involved in mounting immune responses to bacteria. We have designed compounds that block cisplatin's activation of this receptor without affecting its immune function. One aim of this project will be to determine how these compounds exclusively prevent cisplatin activation of the receptor. A second aim will be to develop improved inhibitors of this receptor that disrupt cisplatin toxicity in ear cells. Promising molecules will be tested in zebrafish and mouse models of cisplatin hearing loss. A third aim will examine whether these inhibitors affect the ability of cisplatin to kill cancer cells. We will test this directly on cancer cells, as well as in zebrafish and mouse models where we can directly compare cisplatin tumour killing and toxicity. We will examine alternate routes of co-administering cisplatin and inhibitors, to optimize tumour killing with minimal toxicity. Our research teams consists of experts in molecular biology, mass spectrometry, zebrafish biology, mouse models of hearing and chemistry. The molecules developed in this project that demonstrate an ability to prevent cisplatin toxicity in cells and zebrafish will be moved closer to clinical practice by linkages with a national network examining drug safety in childhood cancer treatment.