Children with the solid tumour neuroblastoma often have metastatic disease in the bone and bone marrow. Relapse with chemoresistant disease is a common occurrence, and there are no curative salvage regimens available for these children. The bone marrow microenvironment is likely to play an important role in drug insensitivity and relapse and tumour-stroma interactions are an attractive target for therapeutic intervention. High throughput screening in a bone marrow-like system might be used to identify small molecule inhibitors that disrupt these interactions or target weaknesses arising from them, and might also be used to flag compounds subject to stromal-mediated resistance in drug development pipelines.
We have conducted a small molecule screen to identify compounds that selectively target neuroblastoma cells in the presence of bone marrow stromal cells. Luciferase-positive neuroblastoma cells were grown both alone (monoculture) and in co-culture with a bone marrow stromal cell line, with neuroblastoma cell viability monitored using bioluminescence. A library of 3700 FDA-approved drugs and bioactive molecules was screened in a 384-well plate format and the viability of neuroblastoma cells compared between monoculture and co-culture.
Several compounds were identified that were substantially more active in the presence of bone marrow stromal cells. Furthermore, several compounds that previously showed promising activity in preclinical animal models of neuroblastoma, conducted using subcutaneous xenografts, were substantially less active in the presence of bone marrow stromal cells. Both types of compounds will now undergo verification by comparing their efficacy in subcutaneous and bone marrow xenograft models to determine whether they are more active in the bone marrow, or subject to stromal-induced drug resistance in vivo.