2019 - Noonan - Cancers.pdf (2.48 MB)

Implementing patient-derived xenografts to assess the effectiveness of cyclin-dependent kinase inhibitors in glioblastoma.

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posted on 11.01.2021, 14:24 by Janis J Noonan, Monika Jarzabek, Frank A Lincoln, Brenton Cavanagh, Arhona R Pariag, Viktorija Juric, Leonie Young, Keith L Ligon, Hanne Jahns, Daniella Zheleva, Jochen Prehn, Markus Rehm, Annette Byrne
Glioblastoma (GBM) is the most common primary brain tumor with no available cure. As previously described, seliciclib, a first-generation cyclin-dependent kinase (CDK) inhibitor, down-regulates the anti-apoptotic protein, Mcl-1, in GBM, thereby sensitizing GBM cells to the apoptosis-inducing effects of the death receptor ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we have assessed the efficacy of seliciclib when delivered in combination with the antibody against human death receptor 5, drozitumab, in clinically relevant patient-derived xenograft (PDX) models of GBM. A reduction in viability and significant levels of apoptosis were observed in vitro in human GBM neurospheres following treatment with seliciclib plus drozitumab. While the co-treatment strategy induced a similar effect in PDX models, the dosing regimen required to observe seliciclib-targeted responses in the brain, resulted in lethal toxicity in 45% of animals. Additional studies showed that the second-generation CDK inhibitor, CYC065, with improved potency in comparison to seliciclib, induced a significant decrease in the size of human GBM neurospheres in vitro and was well tolerated in vivo, upon administration at clinically relevant doses. This study highlights the continued need for robust pre-clinical assessment of promising treatment approaches using clinically relevant models.

Funding

Irish Health Research Board (HRA_POR/2012/88)

EC funded H2020 ITN Grant # 766069 GLIOTRAIN.

History

Associated research data files

Supplementary materials available at: http://www.mdpi.com/2072-6694/11/12/2005/s1

Comments

The original article is available at https://www.mdpi.com/

Published Citation

Noonan JJ, Jarzabek M, Lincoln FA, Cavanagh BL, Pariag AR, Juric V, Young LS, Ligon KL, Jahns H, Zheleva D, Prehn JHM, Rehm M, Byrne AT, Murphy BM. Implementing patient-derived xenografts to assess the effectiveness of cyclin-dependent kinase inhibitors in glioblastoma. Cancers (Basel). 2019;11(12):2005.

Publication Date

12 December 2019

PubMed ID

31842413

Department/Unit

  • Physiology and Medical Physics
  • Surgery

Research Area

  • Neurological and Psychiatric Disorders
  • Cancer

Publisher

MDPI

Version

  • Published Version (Version of Record)

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Royal College of Surgeons in Ireland

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