Antitumor Activity of Radiation Therapy Combined with Checkpoint Kinase Inhibition in SHH/ p53 -Mutated Human Medulloblastoma.

Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Current therapy results in a poor prognosis for high-risk SHH/p53-mutated MB, emphasizing the importance of more effective therapeutic strategies. Here, we investigated the potential radiosensitizing effects of the checkpoint kinase inhibitors (Chk-is) prexasertib (Chk1/2) and SAR-020106 (Chk1) in human SHH/p53-mutated MB in vitro and in vivo. UW228 and DAOY cells were treated with Chk-is and irradiation (RT). Metabolic activity, proliferation, and apoptosis were determined at d3, and long-term clonogenicity was determined at d14. DNA damage was assessed after 1, 24, and 72 h. Patient-derived SHH/p53-mutated, luciferase-transfected MB cells were implanted orthotopically into NSG mice (d0). Fractionated therapy (daily, d7–11) was applied. Body weight (BW) was documented daily, tumor growth weekly, and proliferation at d42. In vitro, Chk-is exhibited a dose-dependent reduction in metabolic activity, proliferation, and clonogenicity and increased apoptosis. A combination of Chk-is with RT enhanced these antitumor effects, including proliferation, apoptosis, and clonogenicity, and increased residual DNA damage compared to RT alone. In vivo, tumor growth was delayed by Chk-is alone. Low-dose prexasertib enhanced RT-induced tumor growth inhibition. High-dose prexasertib and SAR-020106 showed opposite effects, at least at later time points (n = 3). BW assessments revealed that the treatment was well tolerated. Our data indicate a potential benefit of Chk-is in combination with RT in SHH/p53-mutated MB. However, high-dose Chk-is may compromise the RT effect, possibly through anti-proliferative activity. Furthermore, we demonstrate, for the first time, the intracranial antitumor activity of the Chk1-specific inhibitor SAR-020106. [ABSTRACT FROM AUTHOR]