Squamous cell carcinomas arising in patients with recessive dystrophic epidermolysis bullosa are highly aggressive and often cause premature death. Current treatment options are limited, highlighting Show more
Squamous cell carcinomas arising in patients with recessive dystrophic epidermolysis bullosa are highly aggressive and often cause premature death. Current treatment options are limited, highlighting the need for innovative drug development concepts. Through transcriptome-guided computational drug screening, we identified selumetinib, a MAPK/extracellular signal-regulated kinase inhibitor, as a candidate drug for recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas. To verify the therapeutic potential of selumetinib against recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas, we assessed its efficacy in vitro and in vivo. In vitro, selumetinib decreased tumor cell viability, significantly reduced phosphorylation of extracellular signal-regulated kinase, and induced a mesenchymal-to-epithelial phenotypic shift, as indicated by increased E-cadherin and decreased vimentin expression. Functionally, it impaired tumor cell motility and invasion. Moreover, selumetinib significantly decreased PD-L1 and increased major histocompatibility complex class I levels and modulated the expression of immune-related cytokines. In vivo, selumetinib significantly suppressed tumor growth and reduced phosphorylated extracellular signal-regulated kinase levels in xenograft tumors. RNA sequencing identified EGR1 (early growth response protein 1), FOS (fos proto-oncogene), and DUSP6 (dual-specificity phosphatase 6) as candidate biomarkers of treatment response. Selumetinib, identified by computational drug screening, demonstrates efficacy against recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas in vitro and in vivo, suggesting its potential for clinical use. Show less
Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the Show more
Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the selective FGFR1-4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low-grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively. While both EPN patients did not respond to erdafitinib treatment, the FGFR1-ITD-harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6 months after treatment discontinuation. Show less