Implementing Patient-Derived Xenografts to Assess the Effectiveness of Cyclin-Dependent Kinase Inhibitors in Glioblastoma

Noonan, Janis J.; Jarzabek, Monika; Lincoln, Frank A.; Cavanagh, Brenton L.; Pariag, Arhona R.; Juric, Viktorija; Young, Leonie S.; Ligon, Keith L.; Jahns, Hanne; Zheleva, Daniella; Prehn, Jochen H. M.; Rehm, Markus; Byrne, Annette T.; Murphy, Brona M.

doi:10.3390/cancers11122005

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Implementing Patient-Derived Xenografts to Assess the Effectiveness of Cyclin-Dependent Kinase Inhibitors in Glioblastoma

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^1,†

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Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, D02 YN77 Dublin 2, Ireland

Cellular and Molecular Imaging Core, Royal College of Surgeons in Ireland, D02 YN77 Dublin 2, Ireland

Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, D02 YN77 Dublin 2, Ireland

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Department of Oncologic Pathology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA

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Pathobiology Section, School of Veterinary Medicine, University College Dublin, D02 YN77 Dublin 4, Ireland

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Cyclacel Ltd., 1 James Lindsay Place, Dundee, Scotland DD1 5JJ, UK

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Institute of Cell Biology and Immunology, University of Stuttgart, D-70569 Stuttgart, Germany

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Stuttgart Research Center Systems Biology, University of Stuttgart, D-70569 Stuttgart, Germany

Author to whom correspondence should be addressed.

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These authors contributed equally to this work.

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These authors share equal senior authorship.

Cancers 2019, 11(12), 2005; https://doi.org/10.3390/cancers11122005

Received: 20 November 2019 / Revised: 29 November 2019 / Accepted: 1 December 2019 / Published: 12 December 2019

(This article belongs to the Special Issue Tumors of the Central Nervous System: An Update)

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Abstract

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. View Full-Text

Keywords: glioblastoma; CDK inhibitors; seliciclib; CYC065; TRAIL; drozitumab; neurospheres; patient-derived xenograft

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MDPI and ACS Style

Noonan, J.J.; Jarzabek, M.; Lincoln, F.A.; Cavanagh, B.L.; Pariag, A.R.; Juric, V.; Young, L.S.; Ligon, K.L.; Jahns, H.; Zheleva, D.; Prehn, J.H.M.; Rehm, M.; Byrne, A.T.; Murphy, B.M. Implementing Patient-Derived Xenografts to Assess the Effectiveness of Cyclin-Dependent Kinase Inhibitors in Glioblastoma. Cancers 2019, 11, 2005. https://doi.org/10.3390/cancers11122005

AMA Style

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. 2019; 11(12):2005. https://doi.org/10.3390/cancers11122005

Chicago/Turabian Style

Noonan, Janis J., Monika Jarzabek, Frank A. Lincoln, Brenton L. Cavanagh, Arhona R. Pariag, Viktorija Juric, Leonie S. Young, Keith L. Ligon, Hanne Jahns, Daniella Zheleva, Jochen H.M. Prehn, Markus Rehm, Annette T. Byrne, and Brona M. Murphy. 2019. "Implementing Patient-Derived Xenografts to Assess the Effectiveness of Cyclin-Dependent Kinase Inhibitors in Glioblastoma" Cancers 11, no. 12: 2005. https://doi.org/10.3390/cancers11122005

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Implementing Patient-Derived Xenografts to Assess the Effectiveness of Cyclin-Dependent Kinase Inhibitors in Glioblastoma

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