Defining cell-signalling pathways in vismodegib treated basal cell carcinoma
Oncology / Posted 3 years ago
Many cancers have hijacked growth factor receptors and or downstream signalling components through mutations that render the pathway constantly active and so drive cancer cells division. Over the last decade, drugs have been introduced that simultaneously inhibit multiple growth factor pathways (such as tyrosine kinase receptor inhibitors), single pathways (vascular endothelial growth factor receptor, transforming growth factor beta receptor, epidermal growth factor receptor and hedgehog pathway antagonists), mutated targets (B-Raf inhibitors), and downstream signalling targets (MEK inhibitors). While malignancies in patients often demonstrate an initial response to these drugs, cancer recurrence is frequently observed. My group over the last five years has defined cancer stem cells (CaSC) in the two commonest skin cancers, using internationally agreed assays. We have shown in high impact scientific publications that basal cell carcinoma (BCC) CaSC are resistant to both conventional chemotherapy and the recently approved growth factor inhibitor vismodegib. Microarray analysis of treated and untreated BCC CaSC reveals a novel role for the transforming growth factor beta pathway in mediating this resistance. In this proposal we plan to substantiate these findings experimentally and ask if blocking transforming growth factor beta signalling alone or in combination with vismodegib could result in CaSC killing.