Blasting away neuroblastoma
Neuroblastoma is a childhood cancer that can be difficult to treat and is often associated with poor outcomes. To identify therapeutic candidates for this cancer, Hansson et al. screened a large variety of compounds using tumor organoids derived from patients with high-risk neuroblastoma. One of the top hits in this screen was an inhibitor of kinesin spindle protein. The authors demonstrated that this protein is a key dependency in neuroblastoma and that inhibiting it causes numerous abnormalities during cell division, resulting in tumor cell death. In vivo treatment with this inhibitor showed promising results in orthotopic patient-derived xenograft models, including aggressive types associated with poor prognosis.
Abstract
Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that KIF11 is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of MYCN-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.
