Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma

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.

Anti-tumor effects of rigosertib in high-risk neuroblastoma

“…S1 ). In a recent drug screen, we assessed drug sensitivity scores for various compounds against three neuroblastoma PDX models (LU-NB-1, LU-NB-2, and LU-NB-3) relative to human healthy bone marrow cells [17] . There was a more than three-fold increase in the effect of rigosertib on neuroblastoma cells relative to the effect on bone marrow control cells ( Fig.…”

“…In a recent high-throughput drug screen, we identified rigosertib as a potential anti-neuroblastoma agent that displayed high selectivity towards tumor cells compared to healthy bone marrow-derived cells [17] . Recently, Kowalczyk and co-workers also showed that rigosertib can have anti-neuroblastoma effects in conventional in vitro neuroblastoma models [18] .…”

Molecular Mechanisms of MYCN Dysregulation in Cancers

“…These results indicate targeting DNA repair system or drugs causing DNA damage could be synthetic lethal in MYCN -driven tumors. Recent studies reveal various strategies based on N-MYC-mediated synthetic lethality, including glutaminase inhibition or glutamine deprivation ( 157 ), BCL2 inhibition ( 125 ), eliminating SKP2 complexes ( 158 ), kinesin spindle protein (KSP) inhibition ( 159 ), G9a inhibition ( 160 ), poly (ADP-ribose) polymerase (PARP) inhibition ( 161 , 162 ).…”

The Promise of Patient-Derived Preclinical Models to Accelerate the Implementation of Personalised Medicine for Children with Neuroblastoma

“…For example, the triple PIM/PI3K/mTOR inhibitor IBL-302 was used to treat an N-myc expressing neuroblastoma PDX in vivo, in combination with reduced-dose Cisplatin chemotherapy, following extensive in vitro screening [ 79 ]. A panel of MYCN -amplified neuroblastoma organoids was employed to run a high-throughput screen, selecting the inhibitor of kinesin spindle protein, ARRY-520, as an agent to cause reduced organoid viability [ 64 ]. This compound was then further tested preclinically in neuroblastoma N-myc PDX in vivo models, taken from a patient at diagnosis and at treatment-resistant relapse.…”

“…Additional samples may be taken from liquid biopsies, especially including bone marrow aspirates. A dedicated laboratory team should provide expertise in the engraftment of fresh tissue into immunocompromised mice, with or without the parallel establishment of patient tissue as an attached/spheroid/organoid culture [ 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. There are multiple considerations at this step (site of engraftment [ 46 , 55 , 56 , 57 , 59 , 60 , 72 ] strain [ 39 , 40 ]), and experimental protocols should be guided by the ultimate aims of the study.…”