16. Genetic susceptibility and prevention of cisplatin-induced hearing loss in childhood cancer patients

Cisplatin is one of the most essential chemotherapeutic agents for the treatment of a specific subset of pediatric solid tumors and brain tumors. Despite its efficacy, cisplatin-induced hearing loss (CIHL) occurs in about 50% of treated children. Genetic susceptibility may influence the onset of CIHL. Carriership of specific single nucleotide polymorphisms (SNPs) has been reported to be associated with CIHL, mostly identified via candidate gene approaches and Genome-Wide Association Studies. However, more research is needed to fully elucidate the pathophysiological mechanisms of CIHL, which is important to eventually apply otoprotective agents into clinical practice to prevent CIHL as much as possible.

In the current project, the PhD student will therefore investigate the association between mitochondrial DNA (mtDNA) variants, DNA methylation and CIHL development in children with cancer. To date, mtDNA variants have shown to be associated with both maternally inherited non-syndromic and syndromic hearing loss, but they have not been assessed as predictors for CIHL. In addition, DNA methylation is of importance given its fundamental role in gene expression regulation. Up until now, in only one small cohort of cisplatin-treated children DNA methylation seemed to influence susceptibility to hearing loss, which requires further investigation on a larger scale. Furthermore, the current project will focus on investigating the efficacy and safety of sodium thiosulfate (STS), an anti-oxidant that has been previously investigated to prevent CIHL development. The PhD student will study changes in cancer stem cell populations as a result of delayed STS when administered as a chemo-protection agent with cisplatin, and will work on understanding whether or not STS results in altered anti-tumor efficacy of cisplatin in cancer cell lines. The novel insights obtained within this project are highly relevant given the serious impact of CIHL on speech-language development, psychosocial behavior and (future) quality of life of children with cancer.

Necessary skills for this position:

• Master’s degree in: computer sciences; physics; mathematics; artificial intelligence; medical imaging; technical medicine with a strong affinity for programming

• Knowledge on programming skills (essential)

• Knowledge of/willingness to learn clinical background (essential)

• Affinity with medical imaging  (plus)

• Prior knowledge of deep learning (plus)