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Kristian Pietras

Kristian Pietras

Research team manager

Kristian Pietras

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

Author

  • Karin Hansson
  • Katarzyna Radke
  • Kristina Aaltonen
  • Jani Saarela
  • Adriana Mañas
  • Jonas Sjölund
  • Emma M Smith
  • Kristian Pietras
  • Sven Påhlman
  • Krister Wennerberg
  • David Gisselsson
  • Daniel Bexell
Show all

Summary, in English

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.

Department/s

  • LUCC: Lund University Cancer Centre
  • Molecular Pediatric Oncology
  • Division of Translational Cancer Research
  • Experimental oncology
  • Molecular Lymphopoiesis
  • Division of Molecular Hematology (DMH)
  • Pathways of cancer cell evolution
  • Division of Clinical Genetics

Publishing year

2020

Language

English

Publication/Series

Science Translational Medicine

Volume

12

Issue

562

Document type

Journal article

Publisher

American Association for the Advancement of Science (AAAS)

Topic

  • Cancer and Oncology

Status

Published

Project

  • Deciphering and targeting treatment resistant metastatic neuroblastoma

Research group

  • Molecular Pediatric Oncology
  • Experimental oncology
  • Molecular Lymphopoiesis
  • Pathways of cancer cell evolution

ISBN/ISSN/Other

  • ISSN: 1946-6242