Radiosensitisation by olaparib through focused ultrasound delivery in a diffuse midline glioma model
't Hart, E; Bianco, J; Bruin, M A C; Derieppe, M; Besse, H C; Berkhout, K; Chin Joe Kie, L A; Su, Y; Hoving, E W; Huitema, A D R; Ries, M G; van Vuurden, D G
(2023) Journal of controlled release : official journal of the Controlled Release Society, volume 357, pp. 287 - 298
(Article)
Abstract
BACKGROUND AND PURPOSE: Diffuse midline glioma H3K27-altered (DMG) is an aggressive, inoperable, predominantly paediatric brain tumour. Treatment strategies are limited, resulting in a median survival of only 11 months. Currently, radiotherapy (RT), often combined with temozolomide, is considered the standard of care but remains palliative, highlighting the urgency for new
... read more
therapies. Radiosensitisation by olaparib, an inhibitor of PARP1 and subsequently PAR-synthesis, is a promising treatment option. We assessed whether PARP1 inhibition enhances radiosensitivity in vitro and in vivo following focused ultrasound mediated blood-brain barrier opening (FUS-BBBO). METHODS: Effects of PARP1 inhibition were evaluated in vitro using viability, clonogenic, and neurosphere assays. In vivo olaparib extravasation and pharmacokinetic profiling following FUS-BBBO was measured by LC-MS/MS. Survival benefit of FUS-BBBO combined with olaparib and RT was assessed using a patient-derived xenograft (PDX) DMG mouse model. RESULTS: Treatment with olaparib in combination with radiation delayed tumour cell proliferation in vitro through the reduction of PAR. Prolonged exposure of low olaparib concentration was more efficient in delaying cell growth than short exposure of high concentration. FUS-BBBO increased olaparib bioavailability in the pons by 5.36-fold without observable adverse effects. A Cmax of 54.09 μM in blood and 1.39 μM in the pontine region was achieved following administration of 100 mg/kg olaparib. Although RT combined with FUS-BBBO mediated olaparib extravasation delayed local tumour growth, survival benefits were not observed in an in vivo DMG PDX model. CONCLUSIONS: Olaparib effectively radiosensitises DMG cells in vitro and reduces primary tumour growth in vivo when combined with RT. Further studies are needed to investigate the therapeutic benefit of olaparib in suitable preclinical PDX models.
show less
Download/Full Text
Keywords: Blood-brain barrier, Diffuse midline glioma H3K27-altered, Focused ultrasound, PARP1, Radiosensitisation, Pharmaceutical Science, Journal Article
ISSN: 0168-3659
Publisher: Elsevier
Note: Funding Information: This project was supported by KWF Young Investigator Award (KWF 10911, Dr. D.G. van Vuurden). The authors thank Dr. Angel Montero Carcaboso (Sant Joan de Déu Barcelona Hospital, Barcelona, Spain) for kindly providing the patient derived DMG cell lines. We also thank Dr. Wissam Beaino for hosting the experiments at the Radionuclide Center (Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, Amsterdam, Netherlands), Luc Lucas for his technical expertise in LC-MS/MS (Bioanalytical Laboratory of the Pharmacy, Netherlands Cancer Institute, Amsterdam, Netherlands) and Prof. Jan Molenaar for providing plasmids (Princes Máxima Center for Pediatric Oncology, Utrecht, Netherlands). Graphical abstract and Fig. 1 created with BioRender.com Publisher Copyright: © 2023 The Authors
(Peer reviewed)