Induced telomere damage to treat telomerase expressing therapy-resistant pediatric brain tumors

Satarupa Sengupta, Matthew Sobo, Kyungwoo Lee, Shiva Senthil Kumar, Angela R. White, Ilgen Mender, Christine Fuller, Lionel M.L. Chow, Maryam Fouladi, Jerry W. Shay, Rachid Drissi

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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 G2-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.

Original languageEnglish (US)
Pages (from-to)1504-1514
Number of pages11
JournalMolecular Cancer Therapeutics
Volume17
Issue number7
DOIs
StatePublished - Jul 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Sengupta, S., Sobo, M., Lee, K., Kumar, S. S., White, A. R., Mender, I., Fuller, C., Chow, L. M. L., Fouladi, M., Shay, J. W., & Drissi, R. (2018). Induced telomere damage to treat telomerase expressing therapy-resistant pediatric brain tumors. Molecular Cancer Therapeutics, 17(7), 1504-1514. https://doi.org/10.1158/1535-7163.MCT-17-0792