Limited availability of in vivo model systems has hampered efforts to test novel therapies for medulloblastoma, the most common malignant brain tumor that occurs in children. Despite an aggressive combination of surgery, radiation, and chemotherapy, medulloblastoma remains incurable in a significant proportion of patients. Thus, molecularly accurate animal models that replicate the biology of this malignant tumour are urgently needed to develop new therapies that are more effective and less toxic. Orthotopic patient-derived xenograft (PDX) models are considered the gold standard preclinical tool because they retain the genetic features of the original tumour, and the microenvironment of the disease is maintained.
Here we describe the establishment of two new PDX models of medulloblastoma - MB870 and MB913 - developed by direct injection of fresh surgical tissues from children that underwent craniotomy at Princess Margaret Hospital (WA). We determined the tumorigenicity and serial subtransplantability of xenograft tumours, and evaluated histological and immunohistochemical characteristics. Medulloblastoma can be molecularly classified into distinct subgroups. Based on patient age, clinical features and histopathological criteria both PDX models represent non-WNT/non-SHH tumours. Although five-year progression survival rates are 80% overall, patients with non-WNT/non-SHH tumours have reduced survival (60%) indicating current therapies are less effective in this subgroup. Many components of medulloblastoma treatment activate the DNA damage response (DDR) pathway; thus, we hypothesised inhibition of this pathway may sensitise non-WNT/non-SHH medulloblastomas to treatment-induced cell death. To evaluate this, mice harbouring PDX tumours were treated with a CHK1/2 kinase inhibitor either alone or in combination with several conventional agents (cyclophosphamide and gemcitabine). Immunohistochemistry for markers of proliferation (Ki67) and cell death (cleaved caspase 3) in tumours following treatment provided an indication of treatment efficacy, and assessment of DDR pathway effectors accurately indicated drug response.
Animal models that recapitulate the genotypes and phenotypes of medulloblastoma are essential preclinical tools. MB913 and MB870 enable rigorous assessment of new treatments for non-WNT/non-SHH medulloblastoma to identify viable agents for future clinical trials.