Oncotarget

Research Papers:

Inhibition of polo-like kinase 4 (PLK4): a new therapeutic option for rhabdoid tumors and pediatric medulloblastoma

Simone Treiger Sredni _, Anders W. Bailey, Amreena Suri, Rintaro Hashizume, Xingyao He, Nundia Louis, Tufan Gokirmak, David R. Piper, Daniel M. Watterson, Tadanori Tomita

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Oncotarget. 2017; 8:111190-111212. https://doi.org/10.18632/oncotarget.22704

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Abstract

Simone Treiger Sredni1,2,3, Anders W. Bailey1,3,*, Amreena Suri1,3,*, Rintaro Hashizume4, Xingyao He4, Nundia Louis4, Tufan Gokirmak5, David R. Piper5, Daniel M. Watterson6 and Tadanori Tomita1,2

1Ann and Robert H. Lurie Children’s Hospital of Chicago, Division of Pediatric Neurosurgery, Chicago, IL 60611, USA

2Northwestern University, Feinberg School of Medicine, Department of Surgery, Chicago, IL 60611, USA

3Stanley Manne Children’s Research Institute, Cancer Biology and Epigenomics, Chicago, IL 60614, USA

4Northwestern University, Feinberg School of Medicine, Department of Neurological Surgery, Chicago, IL 60611, USA

5Thermo Fisher Scientific, Research and Development, Biosciences Division, Carlsbad, CA 92008, USA

6Northwestern University, Feinberg School of Medicine, Department of Pharmacology, Chicago, IL 60611, USA

*These authors have contributed equally to this work

Correspondence to:

Simone Treiger Sredni, email: ssredni@luriechildrens.org

Keywords: embryonal tumors; CNS; AT/RT; RTK; polyploidy

Received: October 10, 2017    Accepted: November 05, 2017    Published: November 24, 2017

ABSTRACT

Rhabdoid tumors (RT) are highly aggressive and vastly unresponsive embryonal tumors. They are the most common malignant CNS tumors in infants below 6 months of age. Medulloblastomas (MB) are embryonal tumors that arise in the cerebellum and are the most frequent pediatric malignant brain tumors. Despite the advances in recent years, especially for the most favorable molecular subtypes of MB, the prognosis of patients with embryonal tumors remains modest with treatment related toxicity dreadfully high. Therefore, new targeted therapies are needed.

The polo-like kinase 4 (PLK4) is a critical regulator of centriole duplication and consequently, mitotic progression. We previously established that PLK4 is overexpressed in RT and MB. We also demonstrated that inhibiting PLK4 with a small molecule inhibitor resulted in impairment of proliferation, survival, migration and invasion of RT cells.

Here, we showed in MB the same effects that we previously described for RT. We also demonstrated that PLK4 inhibition induced apoptosis, senescence and polyploidy in RT and MB cells, thereby increasing the susceptibility of cancer cells to DNA-damaging agents. In order to test the hypothesis that PLK4 is a CNS druggable target, we demonstrated efficacy with oral administration to an orthotropic xenograft model.

Based on these results, we postulate that targeting PLK4 with small-molecule inhibitors could be a novel strategy for the treatment of RT and MB and that PLK4 inhibitors (PLK4i) might be promising agents to be used solo or in combination with cytotoxic agents.


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