Παρασκευή 13 Απριλίου 2018

Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors

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 (MB). We have previously shown that DIPG, HGG and MB frequently express telomerase activity. Here we show that the telomerase-dependent incorporation of 6-thio-2'deoxyguanosine (6-thio-dG), a telomerase substrate precursor analog, into telomeres leads to telomere dysfunction-induced foci (TIFs) along with extensive genomic DNA damage, cell growth inhibition and cell death of primary stem-like cells derived from patients with DIPG, HGG and MB. 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 G2/M arrest. In vivo, treatment of mice bearing MB xenografts with 6-thio-dG delays tumor growth, increases in-tumor TIFs and apoptosis. Furthermore, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. Together, our findings suggest that 6-thio-dG is a promising novel approach to treat therapy-resistant telomerase-positive pediatric brain tumors.



from Cancer via ola Kala on Inoreader https://ift.tt/2JJ3vXJ
via IFTTT

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου