Exploring potential inhibitors of the HGF-Met signalling pathway as a prospective treatment for paediatric medulloblastoma

Hoyles, NM

Abstract

Understanding the function of the HGF-Met signalling axis could present opportunities for new therapeutic treatments for cancer patients. The brain tumour Medulloblastoma is the leading cause of cancer-related death in children and infants meaning research into better treatment of this cancer is vital. Using cell culture model systems and bioinformatics resources, this project investigated the possible inhibition of c-Met as a potential strategy to improve the treatment options for the childhood cancer medulloblastoma and potentially reduce the impact of late effects on those affected by this form of brain tumour. A panel of known c-Met inhibitors (AMG337, tepotinib and tivantinib) were compared with a panel of novel c-Met inhibitors (JD-1, JD-2, JD-3, JD-4 and JD-5) designed at the University of Salford in order to determine the cytotoxic effect on four medulloblastoma cell lines (ONS76, UW288, Daoy and HD-MB03). However, the novel JD compounds were mostly found to have no cytotoxic effect with the exception of JD-1 and JD-5. In addition, the R2 genomics database was interrogated in order to better understand c-Met as a therapeutic target in medulloblastoma The Cavalli 2017 medulloblastoma expression dataset consisting of 763 patient biopsies was primarily used in order to identify patient characteristics and survival probability linked to high Met expression such as age, gender and sub-group of disease. The SHH medulloblastoma sub-group was found to express the highest average level of Met expression in patients of each medulloblastoma subgroup yet surprisingly these patients also displayed a higher survival probability when Met expression was high. In contrast, in the most aggressive medulloblastoma subgroup Group 3 the survival prognosis was shown to be worse when Met expression was high. The opposite effects that Met expression levels had on each of these sub-groups highlights the importance of patient stratification for the use of Met inhibition as a novel therapeutic strategy for the treatment of medulloblastoma.

Citation

Hoyles, N. Exploring potential inhibitors of the HGF-Met signalling pathway as a prospective treatment for paediatric medulloblastoma. (Dissertation). University of Salford

• Thesis Type: Dissertation
• Deposit Date: Oct 5, 2021
• Publicly Available Date: Oct 5, 2021
• Award Date: Apr 15, 2021