Lay summary
Many cancers that disproportionately affect Māori are caused by amplification, mutation or gene fusions in the Fibroblast Growth Factor Receptor (FGFR) family. Systemic administration of selective FGFR inhibitors is associated with dose-limiting toxicities derived from on-target inhibition of FGFR in normal tissues, requiring dose interruptions and reductions. Consequently, these toxicities compromise efficacy in patients. Consistent with this, the pan-FGFR inhibitor erdafitinib gained accelerated approval in 2019 based on a modest 32% response rate in urothelial carcinoma patients with FGFR2/3 mutations. We have identified a lead FGFR inhibitor prodrug (called SN38180) with the potential to target tumour FGFR-signaling while avoiding systemic toxicities. We will critically evaluate SN38180 in preclinical models of cancer, relative to erdafitinib, and demonstrate the promise of our approach to improve the treatment outcomes for cancer patients with FGFR-dependent disease. The knowledge generated will position SN38180 for clinical development in Aotearoa New Zealand.