Medulloblastoma is the most common malignant brain cancer of childhood. Treatment consists of surgery, followed by radiation therapy (RT) and multi-agent chemotherapy. Although overall survival rates exceed 75%, these rates have not improved for decades and survivors continue to experience debilitating sequelae as a result of their treatment. In the investigation of potential new therapies, our lab recently demonstrated that cell cycle checkpoint kinase (CHK1 and CHK2) inhibitors sensitise medulloblastoma cells to the genotoxic effects of the chemotherapeutics currently used in the clinic. These drugs work mechanistically by impairing the DNA damage response (DDR) pathway. As radiation plays a central role in medulloblastoma treatment, and is also known to activate the DDR pathway, we hypothesised that CHK inhibitors may also boost the effectiveness of RT in medulloblastoma.
To investigate this preclinically we used an XRAD SmART, a unique instrument that combines cone beam CT imaging and rotating x-ray beams, to deliver RT to specifically-defined targets in mouse brain. Mice with orthotopically-implanted medulloblastoma were treated with either RT alone or RT in combination with the CHK inhibitor LY2606368. RT was administered in daily two gray (Gy) fractions up to 24Gy, mimicking clinical protocols, and LY2606368 was administered subcutaneously thrice weekly to replicate plasma concentrations achievable in children. The effect of treatment on animal survival was assessed using Kaplan-Meier analyses, and immunohistochemistry was used to evaluate molecular events such as DNA damage and apoptosis. Tumour-bearing mice receiving combination therapy exhibited significantly increased survival, and this was a result of significantly increased DNA damage and apoptosis in medulloblastoma cells, compared to mice receiving RT alone. It is imperative that only the most effective therapies are translated from the lab to clinical trials. The XRAD SmART is therefore a valuable tool, providing a new opportunity to rigorously evaluate novel drug/radiation combinations, and will facilitate the screening and identification of suitable and effective new treatments for new paediatric cancer clinical trials.