Evaluation of telomere-modifying compound thio as a radiosensitizer and immunomodulator to treat dipg

Abstract Diffuse intrinsic pontine glioma (DIPG) is one of the most aggressive tumors of the central nervous system in children. Radiotherapy remains the only standard treatment but is rarely curative. In recent years, several immunotherapy strategies have emerged as an option to treat DIPG. However, the low mutational burden and rare infiltration of T lymphocytes, render these tumors immunologically “cold” and therefore pose challenges for general immunotherapy. We have previously reported in pediatric brain tumors the preclinical validation of THIO (6-thio-2’-deoxyguanosine), a telomerase substrate precursor analog. Treatment of cancer cells with THIO caused both telomeric and genomic DNA damage and rapid cell death. In vivo treatment delayed tumor growth in mouse models of high-risk medulloblastoma and DIPG. Importantly, THIO crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. The cGAS-STING pathway is a cellular mechanism that senses cytosolic double stranded DNA, stimulating type I interferons (IFNs) and IFN-stimulated genes, thereby activating the innate and adaptive anti-tumor immune responses. Micronuclei resulting from cell division in the presence of unresolved DNA damage, has been shown to be recognized by the cGAS-STING pathway. THIO was shown to induce anti-tumor immunity through micronuclei formation in colon and lung tumor models. We hypothesized that THIO treatment will activate anti-tumor immunity in DIPG. Our results indicate that THIO treatment sensitized DIPG cells to ionizing radiation (IR) leading to a significant decrease in DIPG cell proliferation. We are currently testing this combination in vivo in an orthotopic mouse model of DIPG. We will present results on the potential of THIO to activate anti-tumor immunity through the activation of Sting pathway in a syngeneic mouse model of DIPG. These preclinical studies will support potential use of THIO in combination with IR to treat children with high-risk pediatric brain tumors.