Brain tumours are a varied group of neoplasms affecting both children and adults, being among the cancers with the worst outcome. Neuroblastoma is the most common solid extra-cranial paediatric tumour, accounting for around 15% of paediatric cancer deaths, while glioblastoma is the most aggressive form of brain cancer. Despite multimodal treatment including tumour resection, radiation and chemotherapy, patients often show relapse.
A subpopulation of the tumour cells, cancer stem cells, is resistant to traditional treatment since chemotherapy targets rapidly-proliferating cells, and cancer stem cells are quiescent. Furthermore, due to their undifferentiated and stem-like phenotype, these cells may reinitiate and propagate the tumour.
Therefore, inducing cancer stem cell differentiation would be an efficient way to increase therapy efficacy, since differentiation causes cells to specialise. The specialised cells then age and die naturally. In fact, differentiation therapy with various agents has been tested on both neuroblastoma and glioblastoma. However, in some cases, the neoplasms were subsequently shown to resist drug-induced differentiation. Therefore, new treatment options are needed to target and overcome the current failings of existing therapies.
The proposed approach for achieving differentiation will be to subject the neuroblastoma and glioblastoma cell lines to natural extracts or chemicals that have already produced a differentiating effect on different cancers, or that by virtue of their nature are predicted to potentially induce this differentiating effect on a tumour population.
The degree of differentiation will be determined by means of cell morphology, as well as flow cytometry using antibodies for the specific undifferentiated and differentiated neuroblastoma and glioblastoma cell markers. The most promising differentiation-inducing agents will be used to treat neurospheres of the cell lines. As floating spherical structures of the cell line, the neurospheres more faithfully represent the phenotype and genotype of primary patient tumours compared with serum-derived lines, thus allowing a better understanding of the neoplasms. In addition, the mechanism of action of the best candidate for inducing differentiation will be investigated for further elucidation.
If successful, this study could possibly result in improved therapy and outcomes for patients diagnosed with these debilitating neoplasms.
Ms Giulia Vassallo Eminyan, under the supervision of Dr Pierre Schembri Wismayer, is currently doing this research as part of her PhD studies. She is recipient of a scholarship financed by Alive Charity Foundation through RIDT.
