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

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 G-M arrest. 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..

Telomerase-Mediated Strategy for Overcoming Non–Small Cell Lung Cancer Targeted Therapy and Chemotherapy Resistance

“…S1, B and C ). Our previous studies also showed that human normal fibroblasts, colonic epithelial cells, skin keratinocytes, skin melanocytes, and skin fibroblasts are not as sensitive to 6-thio-dG as telomerase-positive cancer cells and 6-thio-dG causes G2/M arrest in telomerase-positive cells with negligible effect in telomerase-negative cells [14] , [22] , [23] . These results are consistent with the proposed mechanism of action of 6-thio-dG indicating that expression of telomerase in cells increases the sensitivity to 6-thio-dG with minimal effect on normal cells.…”

“…We also showed that targeting telomerase with 6-thio-dG overcame therapy resistance in pediatric brain tumors (demonstrating that 6-thio-dG can cross the blood brain barrier) [24] . In addition, we demonstrated sensitivity to 6-thio-dG in BRAF and checkpoint inhibitor–resistant melanomas [22] , [23] . Here in this study, we extended our preclinical studies to more clinically relevant lung cancer model systems.…”

“…In our previous study, we showed that 6-thio-dG induces apoptosis in telomerase-positive HeLa cervical cancer, pediatric brain tumor (MB004, CCHMC-DIPG1), and melanoma cell lines (A375 and LOX-IMVI BR) [22] , [23] . In this study, we determined the drug response phenotypes across a panel ( n = 43) of NSCLC lines representing a wide variety of lung cancer oncogenotypes; response phenotypes to clinically available drugs; and NSCLCs derived from current, former, and lifetime never smokers.…”

In perspective: An update on telomere targeting in cancer

“…Thus, it is hopeful that 6‐thio‐dG will work as a front line or salvage therapy towards targeting therapy‐resistant cancer cells and may sensitize tumors that are refractory to checkpoint inhibitors providing long‐term durable responses. In a preclinical study on therapy‐resistant pediatric brain tumors, it was also demonstrated that 6‐thio‐dG can cross the blood brain barrier thus expanding the utility of this new approach …”

“…In a preclinical study on therapy-resistant pediatric brain tumors, it was also demonstrated that 6-thio-dG can cross the blood brain barrier thus expanding the utility of this new approach. 45…”