Neuroblastoma (NB), a childhood malignancy of the sympathetic nervous system, remains the leading cause of morbidity and mortality in children. Despite promising initial responses to chemotherapeutic agents, such as vincristine (VCR), ~50% of patients relapse with acquired drug resistance mediated by a myriad of underlying molecular alterations. Several of these diverse pathways remain to be characterised within the context of NB. Key mechanisms include the overexpression of drug efflux pumps, such as ABCB1 (encoding MDR1), alterations of signalling pathways such as PI3K/Akt and Ras-MAPK, and apoptosis inhibition. This project involves firstly analysing the (phospho)proteomic changes underpinning chemoresistance in two paired VCR sensitive and resistant NB cell lines, Kelly and SK-N-AS, before further interrogation of identified protein “hits” using molecular techniques and chemical inhibition. After initial explorations into characterised mechanisms of chemoresistance using the chemical inhibition of apoptosis and drug efflux pathways, (phospho)proteomics data identified the Clk family of splicing kinases as an area of further study. The role of Clk proteins in NB chemoresistance was thus investigated and indicated to affect cell growth and apoptosis in NB cells. Delineating key proteins and pathways involved in the development of chemoresistance highlights novel drug targets within NB and may enable personalised treatment approaches, thus reducing the reliance on toxic chemotherapeutic regimens.
Overcoming drug resistance for efficacious neuroblastoma therapeutics
Charvill, M. E. (Author). 10 Dec 2024
Student thesis: Master's Thesis › Master of Science by Research (MScR)