Back
Full-text
Journal article

A Perspective on Polo-Like Kinase-1 Inhibition for the Treatment of Rhabdomyosarcomas.

  • Gatz SA Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
  • Aladowicz E Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
  • Casanova M Istituto Nazionale dei Tumori, Milan, Italy.
  • Chisholm JC Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
  • Kearns PR Cancer Research UK Clinical Trials Unit (CRCTU), Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
  • Fulda S Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt, Germany.
  • Geoerger B Gustave Roussy Cancer Campus, Department of Paediatric and Adolescent Oncology, Université Paris-Saclay, Villejuif, France.
  • Schäfer BW Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
  • Shipley JM Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, London, United Kingdom.
Show more…
  • 2019-12-12
Published in:
  • Frontiers in oncology. - 2019
PLK1 inhibitors
combination treatment
microtubule disruptors
polo-like kinase 1
rhabdomyosarcomas
English Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/38979
Statistics
Document views: 49 File downloads:
  • Full-text: 0