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Jackson, Mark R. and Richards, Amanda R. and Oladipupo, Abdul-Basit Ayoola and Chahal, Sandeep K. and Caragher, Seamus and Chalmers, Anthony J. and Gomez-Roman, Natividad (2024) ClonoScreen3D - a novel three-dimensional clonogenic screening platform for identification of radiosensitizers for glioblastoma. International Journal of Radiation Oncology, Biology, Physics, 120 (1). pp. 162-177. ISSN 0360-3016

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The ClonoScreen3D platform was demonstrated to be a robust method to screen for single agent and radiation-drug combination activity. Using gold-standard clonogenicity, this assay is a tool for identification of radiosensitizers.

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Abstract

Glioblastoma (GBM) is a lethal brain tumor. Standard of care treatment comprising surgery, radiation and chemotherapy results in median survival rates of 12-15 months. Molecular targeted agents identified using conventional two-dimensional (2D) in vitro models of GBM have failed to improve outcome in patients, rendering such models inadequate for therapeutic target identification. A previously developed 3D GBM in vitro model that recapitulates key GBM clinical features and responses to molecular therapies was investigated for utility for screening novel radiation-drug combinations using gold-standard clonogenic survival as readout. Patient-derived GBM cell lines were optimized for inclusion in a 96-well plate 3D clonogenic screening platform, ClonoScreen3D. Radiation responses of GBM cells in this system were highly reproducible and comparable to those observed in low-throughout 3D assays. The screen methodology provided quantification of candidate drug single agent activity (EC ) and the interaction between drug and radiation (radiation interaction ratio, RIR). The PARP inhibitors talazoparib, rucaparib and olaparib, each showed a significant interaction with radiation by ClonoScreen3D and were subsequently confirmed as true radiosensitizers by full clonogenic assay. Screening a panel of DNA damage response inhibitors revealed the expected propensity of these compounds to interact significantly with radiation (13/15 compounds). A second screen assessed a panel of compounds targeting pathways identified by transcriptomic analysis and demonstrated single agent activity and a previously unreported interaction with radiation of dinaciclib and cytarabine (RIR 1.28 and 1.90, respectively). These compounds were validated as radiosensitizers in full clonogenic assays (sensitizer enhancement ratio 1.47 and 1.35, respectively). The ClonoScreen3D platform was demonstrated to be a robust method to screen for single agent and radiation-drug combination activity. Using gold-standard clonogenicity, this assay is a tool for identification of radiosensitizers. We anticipate this technology will accelerate identification of novel radiation-drug combinations with genuine translational value. [Abstract copyright: Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.]

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Jackson, Mark R.

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Richards, Amanda R.

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Oladipupo, Abdul-Basit Ayoola

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Chahal, Sandeep K.

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Caragher, Seamus

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Chalmers, Anthony

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Williamson, Aoife and Houston, Peter and Paterson, Jennifer and Chalmers, Anthony J. and McLoone, Philip and Fullerton, Natasha and Foo, Sin Yee and James, Allan and Nowicki, Stefan (2024) Dosimetric comparison of hippocampal sparing technologies in patients with low grade glioma. Neuro-Oncology Advances, 6 (1): vdae131. ISSN 2632-2498

Boele, Florien and Rosenlund, Lena and Nordentoft, Sara and Melhuish, Sara and Nicklin, Emma and Rydén, Isabelle and Williamson, Aoife and Donders-Kamphuis, Marike and Preusser, Matthias and Le Rhun, Emilie and Kiesel, Barbara and Minniti, Giuseppe and Furtner, Julia and Dirven, Linda and Taphoorn, Martin and Galldiks, Norbert and Rudà, Roberta and Chalmers, Anthony and Short, Susan C. and Piil, Karin and the Nurse and Allied Health Professionals Committee and the Disparity and Inclusion Committee of EANO (2024) Inequalities in access to neuro-oncology supportive care and rehabilitation: a survey of healthcare professionals’ perspectives. Neuro-Oncology Practice, 11 (4). pp. 484-493. ISSN 2054-2577

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Gomez-Roman, Natividad

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Copyright: © 2024 The Author(s)

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Elsevier

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166:171

166:171

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Information

Title:

ClonoScreen3D - a novel three-dimensional clonogenic screening platform for identification of radiosensitizers for glioblastoma

Creators:

Jackson, Mark R. and Richards, Amanda R. and Oladipupo, Abdul-Basit Ayoola and Chahal, Sandeep K. and Caragher, Seamus and Chalmers, Anthony J. and Gomez-Roman, Natividad

Identification Number:

10.1016/j.ijrobp.2024.02.046

Date:

1 September 2024

Divisions:

College of Medical Veterinary and Life Sciences > School of Cancer Sciences

Publisher:

Elsevier

Additional Information:

This work was funded by an NC3Rs grant (grant ref: NC/P001335/1) awarded to N.G.-R. and A.J.C. Additional support was provided by the Cancer Research UK Radiation Research Centre of Excellence at the University of Glasgow (C16583/A28803).

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URI:

https://pub.demo35.eprints-hosting.org/id/eprint/166

Item Type:

Article

Depositing User:

Unnamed user with email ejo1f20@soton.ac.uk

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Users 37347 not found.

Date Deposited:

11 Jun 2025 16:35

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