Targeting cancer stem cells
Glioblastoma multiforme (GBM) is the most common malignant intracranial tumour in adults. Significant progress has been made with respect to determining the associated genetic alterations and surgical treatment. However, this has translated into little improvement in patient median survival overall. Emerging evidence indicates that a sub-population of cancer cells possess stem cell-like properties and could thus be responsible for tumour development, maintenance and drug resistance. Given the aggressive nature of GBM and the poor survival, novel treatment strategies are urgently required. Scientists on the EU-funded NOTCH PATHWAY IN GSC (Role of Notch signaling pathway in glioma stem cells) project proposed to investigate the role of the Notch signalling pathway in GBM. Notch signalling is known to be involved in normal neural stem cells and an overactive pathway has been linked with GBM. It therefore represents a putative therapeutic target against GBM. In this context, the consortium isolated stem cells from patients with GBM to find a highly active Notch signalling pathway. They discovered that Notch signalling was partly induced by TGFβ, a molecule implicated in the maintenance of GBM stem cells. Scientists activated the Notch pathway in patient-derived cultures and discovered that it upregulated stem cell markers such as CD44. A decrease in GBM stem cells was seen upon Notch inhibition with a γ-secretase inhibitor, clearly underscoring the involvement of Notch in cell survival. The reduction in stem cells was even more pronounced when a combination of Notch and TGFβ receptor inhibitors were used at the same time. Taken together, the results of the NOTCH PATHWAY IN GSC study demonstrate the interplay between Notch and TGFβ signalling in the maintenance of GBM stem cells. The consortium is confident that a combinatorial targeting of these two pathways will be more therapeutically beneficial than either of these treatments used alone.
Keywords
Cancer stem cells, glioblastoma multiforme, Notch, TGFβ, receptor inhibitor
