Targeting calcium signalling pathways to control medulloblastoma

Background: Medulloblastoma (MB) is the most common malignant childhood brain tumour. MB contains four molecular subgroups of WNT, SHH, Group 3 and Group 4. Groups 3 and 4 (accounting for >60% of all MBs) are associated with high metastasis and poor patient survival rate of around 60%. Due to the harsh nature of current treatments (surgery, radio/chemotherapy), children who survive the cancer often show impaired physical and cognitive function. There is therefore a clear need for new treatment options for these aggressive MBs. Calcium ion is an intracellular messenger involved in a variety of cellular processes from gene expression to cell growth and death. Calcium signalling is also widely implicated in a variety of the cancer hallmarks including proliferation, angiogenesis and metastasis are regulated by calcium signalling.

Methods: Gene expression of calcium transporters were evaluated in in-silico analysis of tumours from four molecular subgroups. Expression of transporters with higher levels in aggressive Groups 3/4 MB were further correlated with metastasis and patient survival rates. In-vitro analysis assessed the effect of pharmacological inhibition of selected transporters on cell proliferation (WST-1 assay), metabolism (ATP assay), cologenicity and sphere formation ability of MB cells.

Results: in-silico analysis revealed overexpression of specific calcium channels in Groups 3 and 4 MB and their correlation with metastasis and patient survival rates. In-vitro analysis of a member of the transient-receptor potential (TRP) channels (as one of the identified transporters from the in-silico analysis), demonstrated its upregulation in MB cell lines corresponding to Groups 3 and 4. Pharmacological inhibition of this channel, concentration- dependently inhibited proliferation of D341 cells and sphere formation of CHLA-01R-MED cells.

Conclusion: These studies identified specific calcium channels as potential critical proteins in MB progression. Further studies are warranted to evaluate the potential of targeting these proteins for the control of MB