PNR-31
INHIBITING CELL CYCLE CHECKPOINTS IMPROVES THE EFFICACY OF CHEMOTHERAPY IN PINEOBLASTOMA

Pineoblastoma is an invasive embryonal brain tumour arising in the pineal gland. Although pineoblastoma and other CNS PNETs are biologically distinct from medulloblastoma, due to histologic similarities older children with pineoblastoma have been treated with medulloblastoma regimens: upfront surgery followed by cranio-spinal irradiation and platinum-/alkylator-based chemotherapy. Infants with pineoblastoma have been treated utilising intensive chemotherapy only strategies to avoid the damaging effects of radiotherapy on developing brain. Whilst outcome for older children is comparable to medulloblastoma, it is dismal in infants. A lack of preclinical models has hindered development of more effective therapies for pineoblastoma. We previously isolated three cell lines from tumour tissue obtained at two separate surgeries from an 8-month-old girl with extensive pineoblastoma. With the aim of repurposing therapeutics, we performed a high-throughput screen of 3915 compounds, including FDA-approved and oncology drugs. This identified 38 effective compounds with diverse mechanisms of action compared to the current drugs used in the clinic. We have further characterised the interactions of several of these compounds with the conventional chemotherapeutics used for treatment. This revealed that several inhibitors targeting cell cycle regulatory kinases enhanced the efficacy of cyclophosphamide. These drug combinations are currently being examined for efficacy in vivo using orthotopic xenograft mouse models. Thus, high-throughput drug screening and in vitro assessment of novel drugs in patient-derived brain tumour cells can identify potential new therapies. Assessment of new drug combinations in mouse models will enable the exclusion of potentially ineffective treatments and prioritisation of truly beneficial new treatments for clinical trial.