Targeting TERT and the MYCN gene network as a novel therapeutic approach for high-risk neuroblastoma
MYCN belongs to a small family of transcription factors implicated in fundamental cellular processes. There are 3 members of the MYC family in mammalian cells, c-MYC, MYCN and L-MYC. They interact with DNA through a consensus sequence called the E-box (CANNTG) and in concert with the partner MAX facilitate gene transcription. The importance of MYC in cell biology is vast. MYC controls key cellular processes including proliferation, survival and metabolism. Critical to this proposal is the fact that one of the genes positively regulated by MYC is the catalytic subunit of the telomerase complex, TERT . A recent study has shown that genomic rearrangements near the TERT gene are frequent in high-risk neuroblastomas and activation of TERT is particularly frequent in MYCN amplified tumours. These results are supported by our own analysis suggesting that the expression of TERT is significantly predictive of poor prognosis in multiple neuroblastoma datasets.
The central objective of the study is to verify whether inhibition of TERT by a clinically viable inhibitor called Imetelstat and using Fluoxetine-Prozac to inhibit the MYCN signalling network can cause synergistic killing of high-risk, MYCN amplified neuroblastoma cells. In vitro studies: neuroblastoma cell lines will be exposed to increasing concentrations of Imetelstat, Prozac and drug combinations for 24-72 hours and the IC50 will be calculated using MTT/MTS assays. The different cell lines will also be subjected to immunofluorescence analysis with activated caspase-3 antibody, propidium iodide staining and FACS analysis to determine the cell cycle and apoptosis status. In vivo studies: it will be verified if Imetelstat can cause regression of human neuroblastoma tumours transplanted into immunocompromised mice.
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