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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • University of Copenhagen
  • University of Helsinki
  • Skåne University Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Artikelnummereaba4434
TidskriftScience Translational Medicine
Volym12
Utgåva nummer562
StatusPublished - 2020
PublikationskategoriForskning
Peer review utfördJa

Relaterad forskningsoutput

Karin Hansson, 2020, Lund: Lund University, Faculty of Medicine. 74 s.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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Related projects

Daniel Bexell, Kristina Aaltonen, Karin Hansson & Javanshir Esfandyari

Swedish Research Council, Cancerfonden, Kungliga Fysiografiska Sällskapet i Lund

2018/01/01 → …

Projekt: Forskning

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