MB-75: EXPLOITING THE CELL CYCLE TO IMPROVE TREATMENT EFFICACY IN MEDULLOBLASTOMA

Medulloblastoma is the most common malignant brain cancer of childhood. It arises in the cerebellum and has a predilection to spread throughout the central nervous system. The most effective treatment is a combination of surgery, followed by radiotherapy and intensive cytotoxic chemotherapy; however, devastating long-term sequelae, due to the collateral damage of healthy tissue by these treatments, including developmental defects, psychosocial deficits and secondary tumours are frequently encountered by survivors, and for patients with metastatic disease prognosis are dismal. Using high-throughput, cell-based assays human medulloblastoma cells (n = 6) were screened against a library of approximately 3200 compounds. Fifty effective compounds were identified and further in vitro assessment identified several drugs that enhanced the cytotoxic activity of clinically-used chemotherapeutics: cyclophosphamide, cisplatin, and gemcitabine. Cell cycle checkpoint kinase (CHK1/2) inhibitors (iCHKs), were further assessed in vivo using mice bearing intracranial implants of human medulloblastoma cells. When combined with DNA-damaging chemotherapeutics, iCHK treatment reduced tumour burden as measured by bioluminescence imaging and significantly increased survival of animals with medulloblastoma up to three-fold, in several different PDX models. Immunohistochemical assessment of tumours showed the combination treatment significantly decreased tumour proliferation and significantly induced apoptosis compared with controls. These data demonstrate our experimental approach has robustly identified effective new therapies for paediatric medulloblastoma, and our findings strongly suggest CHK1/2 inhibitors have promising potential to improve treatments for this disease.