Medulloblastoma is a metastatic paediatric brain tumour arising in the cerebellum, which also occasionally occurs in adults. It is classified into four major subgroups based on clinical and molecular profiles. Certain sub-groups, namely those with SHH with p53 mutations and Group 3 with MYC amplification, have dismal prognoses. Surgical resection and craniospinal irradiation followed by chemotherapy are the mainstay of medulloblastoma treatment. Unfortunately, life-long medical problems that result from the collateral damage of healthy tissue by these treatments significantly impact patient quality of life, and despite treatment intensification, survival has plateaued for the past two decades at around 70%. Safer, more effective therapeutic approaches for these patients are desperately needed.
We used a high-throughput, cell-based assay to identify compounds that target medulloblastoma, and enhance the cytotoxicity of current treatments. We identified prexasertib, an inhibitor of the cell cycle checkpoint kinases 1 and 2 (Chk1/2), as a promising candidate. Chk1/2 are critical regulators of the DNA-damage response. Our laboratory has previously shown that prexasertib enhances the cytotoxic activity of the clinically-used DNA-damaging drugs cyclophosphamide, cisplatin and gemcitabine. Given radiation is a potent inducer of DNA damage, we hypothesised that Chk1/2 inhibition with prexasertib may enhance radiation-induced cytotoxicity in medulloblastoma.
Prexasertib treatment in vitro reduced the colony-forming ability of medulloblastoma cells post-irradiation. In vivo, tumour-targeted radiation therapy and prexasertib each induced modest apoptosis in orthotopically-implanted medulloblastomas, which was significantly increased when co-administered. Importantly, this combination therapy also improved the survival of mice with medulloblastoma. Taken together, these data reveal significant anti-tumour effects when radiation is combined with Chk1/2 inhibition, suggesting that this combination therapy may increase treatment efficacy.