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Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma
Karin Hansson1, Katarzyna Radke1, Kristina Aaltonen1
1Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, 223 81 Lund, Sweden.
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.
Insights
Kinesin spindle protein (KSP) inhibition shows promise for treating high-risk neuroblastoma. This approach targets MYCN-amplified tumors, reducing viability and causing tumor regression in preclinical models.
Area of Science:
- Pediatric Oncology
- Cancer Therapeutics
- Molecular Biology
Background:
- Neuroblastoma, a high-risk childhood cancer, frequently relapses despite aggressive treatment.
- MYCN amplification is a key driver in aggressive neuroblastoma, necessitating novel therapeutic strategies.
- Existing treatments for high-risk neuroblastoma have limited efficacy, highlighting the need for new drug targets.
Purpose of the Study:
- To identify novel anti-neuroblastoma drugs using a high-throughput screen of human tumor organoids.
- To investigate the therapeutic potential of kinesin spindle protein (KSP) inhibition in MYCN-amplified neuroblastoma.
- To evaluate the efficacy of KSP inhibition in preclinical neuroblastoma models.
Main Methods:
- High-throughput drug screening of human MYCN-amplified neuroblastoma organoids.
- Genome-scale loss-of-function screens to identify essential genes for neuroblastoma viability.
- In vitro studies using patient-derived xenograft (PDX) cells and in vivo studies in mouse models.
Main Results:
- Identification of ARRY-520, a KSP inhibitor, with significant anti-neuroblastoma effects.
- KIF11 (KSP-encoding gene) is crucial for neuroblastoma cell viability and associated with poor prognosis.
- KSP inhibition induced mitotic arrest, apoptosis, and tumor regression in preclinical neuroblastoma models, improving survival.
Conclusions:
- Kinesin spindle protein (KSP) inhibition represents a promising therapeutic strategy for high-risk, MYCN-amplified neuroblastoma.
- Targeting KSP effectively reduces tumor burden and improves survival in preclinical models.
- Further clinical investigation of KSP inhibitors is warranted for pediatric neuroblastoma treatment.
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