THER-10. TELOMERE TARGETING BASED-THERAPIES TO TREAT THERAPY-RESISTANT PEDIATRIC BRAIN TUMORS. (23rd April 2019)

• Record Type: Journal Article
• Authors: Sengupta, Satarupa; Kumar, Shiva Senthil; Mishra, Deepak; Drissi, Rachid
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 2
• Page Start: ii116
• Page End: ii116
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.217
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Resistance to conventional therapies is the biggest challenge to cure high-risk pediatric brain tumors, the leading cause of cancer-related death in children. Therefore, developing effective therapies is an urgent unmet need. We recently reported in pediatric brain tumors the preclinical validation of 6-thio-dG, a telomerase substrate precursor analog*. Treatment with 6-thio-dG caused both telomeric and genomic DNA damage, G2 /M cell cycle arrest and rapid cell death. In vivo treatment delayed tumor growth in mouse models of high-risk medulloblastoma and DIPG. Furthermore, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. In vitro, the effect of 6-thio-dG was sustained several days post-drug removal, suggesting that a short exposure time in a clinical setting may be sufficient to have a therapeutic effect. While the majority of the 6-thio-dG treated cells died by apoptosis, survivor cells emerged after prolonged drug holiday in both group 3 medulloblastoma and DIPG patient-derived cells. These findings suggest that in the long term, DIPG and medulloblastoma will likely resist to 6-thio-dG monotherapy. We will present preclinical data and discuss telomere targeting based-therapies in combination with radiotherapy (RT) and G2 /M checkpoint inhibitors. Together, our data indicate that telomere targeting is an effective and a rapid therapy, and suggest that the combination with RT or G2 /M checkpoint inhibitors will prevent the emergence of resistant cells and disease recurrence. *Sengupta, S. et al. Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors, Mol Cancer Ther, 2018.