THE BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM
发明人:
SHAY, Jerry
申请号：
USUS2019/023596
公开号：
WO2019/183482A1
申请日:
2019.03.22
申请国别(地区):
US
年份:
2019
代理人:
摘要：
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. 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). It has shown that DIPG, HGG and MB frequently express telomerase activity. It is now shown 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, these findings suggest that 6-thio-dG is a promising approach to treat therapy -resistant telomerase-positive pediatric brain tumors.Les tumeurs cérébrales restent la cause principale de décès liés au cancer chez les enfants et, chez les survivants des traitements actuels, sont souvent associées à des séquelles à long terme. La télomérase et les télomères jouent un rôle important dans le cancer, et représentent des cibles thérapeutiques intéressantes pour traiter des enfants atteints de tumeurs cérébrales de mauvais pronostic telles que le gliome diffus du tronc cérébral de l'enfant (DIPG, pour "diffuse intrinsic pontine glioma"), le gliome de haut grade (HGG, pour "high-grade glioma")
