TY - JOUR
T1 - Induced telomere damage to treat telomerase expressing therapy-resistant pediatric brain tumors
AU - Sengupta, Satarupa
AU - Sobo, Matthew
AU - Lee, Kyungwoo
AU - Kumar, Shiva Senthil
AU - White, Angela R.
AU - Mender, Ilgen
AU - Fuller, Christine
AU - Chow, Lionel M.L.
AU - Fouladi, Maryam
AU - Shay, Jerry W.
AU - Drissi, Rachid
N1 - Funding Information:
This work was supported by CancerFree KIDS Pediatric Cancer Research Alliance (to R. Drissi and S. Sengupta), by the Division of Oncology, and by the Brain Tumor Center, Cincinnati Children's Hospital Medical Center. We thank D.D. Bigner (Duke University) for kindly providing us with D-425 and D-458 cell lines, Y.-J. Cho (Oregon Health & Science University) for MB004 cell line, X.-N. Li (Baylor College of Medicine) for R0315-GBM cell line, M. Monje (Stanford University) for SU-DIPG-VI cell line, and N. Oatman and B. Dasgupta (CCHMC) for technical assistance and for luciferase labeling of CCHMC-DIPG-1 cells. We thank the Comprehensive Mouse and Cancer Core, and J. Mulloy laboratory, CCHMC for providing the Athymic Ncr-nu/nu and NRG mice, respectively.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/7
Y1 - 2018/7
N2 - 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 2 -M arrest. In vivo treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and 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.
AB - 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 2 -M arrest. In vivo treatment of mice bearing medulloblastoma xenografts with 6-thio-dG delays tumor growth and 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.
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U2 - 10.1158/1535-7163.MCT-17-0792
DO - 10.1158/1535-7163.MCT-17-0792
M3 - Article
C2 - 29654065
AN - SCOPUS:85049466607
SN - 1535-7163
VL - 17
SP - 1504
EP - 1514
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 7
ER -