Pineoblastoma is an invasive embryonal brain tumour arising in the pineal gland of children. Since they are rare, limited clinical trials specific for these patients have been performed. As such, pineoblastoma patients receive the same treatment as medulloblastoma, another more common embryonal brain cancer, however the biology and behaviour of these tumours is known to be diverse. As a consequence, the outcomes of children with pineoblastoma are significantly worse, with survival rates of approximately 65%. Improved therapies for pineoblastoma are urgently needed. A lack of preclinical models has hindered development of more effective therapies for pineoblastoma. We previously isolated two cell lines from separate surgical samples from an 8-month-old girl with extensive pineoblastoma. The cells robustly form pineoblastoma upon intracranial implantation in mice. With the aim of repurposing therapeutics, we performed a high-throughput drug screen that identified DNA damage response inhibitors, especially cell cycle checkpoint kinase 1 and 2 (CHK1/2) inhibitors as promising candidates for pineoblastoma treatment. Here, we demonstrate a synergistic interaction of these inhibitors with conventional pineoblastoma chemotherapies both in vitro and in vivo. CHK1/2 inhibitors were found to impair cell cycle arrest after chemotherapy-induced DNA damage, increasing pineoblastoma cell death in vitro. Importantly an increase in both DNA damage and apoptosis was observed in vivo when CHK1/2 inhibitors were combined with DNA-damaging chemotherapy, and mice with orthotopic pineoblastoma exhibited significantly extended survival. Our data show that this could be an effective new therapeutic combination for paediatric pineoblastoma and suggests patients may benefit from inclusion in the upcoming SJ-ELiOT clinical trial combining the CHK1/2 inhibitor prexasetib with conventional chemotherapies.
Andradas Arias and Dholaria contributed equal