Abstract Diffuse midline gliomas (DMG) including diffuse intrinsic pontine glioma (DIPG) are among the deadliest and most treatment refractory cancers in children with median overall survival 1 year for DIPG. Radiotherapy (RT) remains the standard of care, minimally improves the overall survival by only 3-4 months in average and often is associated with devastating side effects. Moreover, these tumors have been described as a “cold” due to lack of inflammatory microenvironment and minimal immune cells infiltration preventing tumor recognition by the immune system. Thus, it is crucial to find new therapies that improve outcomes, reduce RT side effects, and boost immune-mediated tumor targeting. Here, our preclinical data have demonstrated that the telomerase-dependent telomeric incorporation of THIO (6-thio-2’deoxyguanosine), a nucleoside analog, leads to telomere dysfunction-induced foci (TIF) along with extensive genomic DNA damage, and activation of ATR and ATM pathways resulting in G2/M cell cycle arrest in in vitro DIPG models. Importantly, we have demonstrated that THIO crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG, leading to increased in-tumor TIF and apoptosis. Furthermore, THIO synergistically sensitizes DIPG cells to ionizing radiation (IR) in vitro, while the combination of THIO and IR in vivo, significantly decreased tumor growth and extended survival. To further increase the anticancer efficacy, we used ATR and ATM inhibitors in combination with THIO to prevent damaged cells from remaining in G2/M and thus, eliciting increased cell apoptosis. Moreover, combination with these inhibitors enhanced THIO-dependent induction of micronuclei formation leading to cGAS-STING pathway activation in DIPG cells. Together, these findings provide a strong rationale for the combination of THIO and RT to improve outcome and minimize the RT side effects to treat children with DMG.
Umaru et al. (Fri,) studied this question.