alpha-2--deoxythioguanosine and Brain-Stem-Neoplasms

Brain tumors remain the leading cause of cancer-related deaths in children and often are associated with long-term sequelae among survivors of current therapies. Hence, there is an urgent need to identify actionable targets and to develop more effective therapies. Telomerase and telomeres play important roles in cancer, representing attractive therapeutic targets to treat children with poor-prognosis brain tumors such as diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), and high-risk medulloblastoma. We have previously shown that DIPG, HGG, and medulloblastoma frequently express telomerase activity. Here, we show that the telomerase-dependent incorporation of 6-thio-2'deoxyguanosine (6-thio-dG), a telomerase substrate precursor analogue, into telomeres leads to telomere dysfunction-induced foci (TIF) along with extensive genomic DNA damage, cell growth inhibition, and cell death of primary stem-like cells derived from patients with DIPG, HGG, and medulloblastoma. Importantly, the effect of 6-thio-dG is persistent even after drug withdrawal. Treatment with 6-thio-dG elicits a sequential activation of ATR and ATM pathways and induces G

Topics: Animals; Brain Neoplasms; Brain Stem Neoplasms; Cell Line, Tumor; Cell Proliferation; Deoxyguanosine; DNA Damage; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glioma; Humans; Medulloblastoma; Mice; Neoplastic Stem Cells; Prognosis; Telomerase; Telomere; Thionucleosides; Xenograft Model Antitumor Assays