USE OF 6-THIO-dG TO TREAT THERAPY-RESISTANT TELOMERASEPOSITIVE 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. 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.

Description

PRIORITY CLAIM[0001]This application claims benefit of priority to U.S. Provisional Application Ser. No. 62 / 646,820, filed Mar. 22, 2018, the entire contents of which are hereby incorporated by reference.BACKGROUND1. Field[0002]The present disclosure relates to the fields of medicine, pharmacology, molecular biology and oncology. More particular, the disclosure relates to methods and compositions for treating pediatric brain cancers, such as drug-resistant brain cancers.2. Related Art[0003]Telomeres are the physical ends of eukaryotic linear chromosomes and, in mammals, are composed of several kilobases of tandem TTAGGG repeats that are bound by the shelterin protein complex (1). Shelterin proteins protect telomeres from ATM and ATR-dependent DNA damage responses (DDR) (1). The inventors and others have previously shown that natural telomere shortening during replicative senescence or experimental telomere uncapping elicit ATM-dependent DDR triggered by telomere dysfunction (2,3). T...

AI Technical Summary

Benefits of technology

The patent describes methods for treating brain cancer in children using a drug called 6-thio-2′deoxyguanosine (6-thio-dG), which can induce cell cycle arrest and inhibit the growth of cancer cells. The method can also be combined with other drugs or therapies such as immunotherapy or chemotherapy. The patent also provides a method for assessing the effects of 6-thio-dG on brain cancer cells. Overall, the patent offers a potential new treatment for brain cancer in children that targets the disease's underlying biology.

Problems solved by technology

The regimen proved intolerable, because of thrombocytopenia that led to bleeding.

Because targeting telomerase directly, such as with imetelstat, would result in a significant lag period from the initiation of treatment until telomeres shortened sufficiently to reduce tumor burden, stopping therapy with imetelstat would result in rapid telomere regrowth.

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