Neurosurgical application of olaparib from a thermo-responsive paste potentiates DNA damage to prolong survival in malignant glioma

Serra, Riccardo; Smith, Stuart J.; Rowlinson, Jonathan; Gorelick, Noah; Moloney, Cara; McCrorie, Phoebe; Veal, Gareth J.; Berry, Philip; Chalmers, Anthony J.; Suk, Ian; Shakesheff, Kevin M.; Alexander, Cameron; Grundy, Richard G.; Brem, Henry; Tyler, Betty M.; Rahman, Ruman

Abstract

Background: There is increased pan-cancer specific interest in repurposing the poly adenosine diphosphate-ribose polymerase-1 (PARP-1) inhibitor, olaparib, for newly diagnosed or recurrent isocitrate dehydrogenase wild type glioblastoma. We explore whether intra-cavity delivery of olaparib confers a survival benefit in a pre-clinical high-grade glioma model. Methods: Primary tumor RNA sequencing data was used to determine PARP-1 as a target in the glioblastoma infiltrative margin. We assessed radiosensitization conferred by olaparib alone and concomitant to genotoxic insults in vitro using clonal growth assays, cell cycle analysis and immunocytochemistry, and in vivo upon post-surgical delivery from a temperature-sensitive polymeric paste. Results: RNA-sequencing confirmed PARP-1 as a viable therapy target in glioblastoma infiltrative disease. Acute exposure of glioma cells to olaparib impaired proliferation and induced late-stage apoptosis associated with DNA damage in vitro, potentiated by radiation. Using high-grade glioma orthotopic allografts, a long-term overall survival benefit was observed upon interstitial olaparib delivery concomitant with radiotherapy, compared to systemic olaparib and standard glioblastoma treatment. Combined delivery of olaparib with either temozolomide or etoposide increased long-term survival, suggestive of olaparib functioning as DNA damage sensitizer. Conclusions: Collectively, our data support a rationale for localized olaparib delivery concomitant with the current clinical regimen for malignant glioma treatment.

Citation

Serra, R., Smith, S. J., Rowlinson, J., Gorelick, N., Moloney, C., McCrorie, P., Veal, G. J., Berry, P., Chalmers, A. J., Suk, I., Shakesheff, K. M., Alexander, C., Grundy, R. G., Brem, H., Tyler, B. M., & Rahman, R. (2024). Neurosurgical application of olaparib from a thermo-responsive paste potentiates DNA damage to prolong survival in malignant glioma. British Journal of Cancer, 131, 1858-1868. https://doi.org/10.1038/s41416-024-02878-2

• Journal Article Type: Article
• Acceptance Date: Oct 4, 2024
• Online Publication Date: Oct 22, 2024
• Publication Date: Oct 22, 2024
• Deposit Date: Oct 22, 2024
• Publicly Available Date: Oct 23, 2024
• Journal: British Journal of Cancer
• Print ISSN: 0007-0920
• Electronic ISSN: 1532-1827
• Publisher: Cancer Research UK
• Peer Reviewed: Peer Reviewed
• Volume: 131
• Pages: 1858-1868
• DOI: https://doi.org/10.1038/s41416-024-02878-2
• Keywords: CNS cancer; Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/40856364
• Publisher URL: https://www.nature.com/articles/s41416-024-02878-2
• Additional Information: Received: 21 May 2024; Revised: 1 October 2024; Accepted: 4 October 2024; First Online: 22 October 2024; : Dr Henry Brem is a paid consultant to Insightec and chairperson of the company’s Medical Advisory Board. Insightec is developing focused ultrasound treatments for brain tumors. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict-of-interest policies. Dr Brem receives research funding from NIH, Johns Hopkins University, Khatib Foundation, NICO Myriad Corporation, and philanthropy. He is a consultant for Accelerating Combination Therapies, Insightec, Candel Therapeutics, Inc., Catalio Nexus Fund II, LLC, LikeMinds, Inc*, Galen Robotics, Inc.* CraniUS*, and Nurami Medical*. Betty Tyler has research funding from NIH and is a co-owner for Accelerating Combination Therapies*. Ashvattha Therapeutics Inc. has also licensed one of her patents and she is a stockholder for Peabody Pharmaceuticals (*includes equity or options).; : All animals (live vertebrates) were treated in accordance with the policies and guidelines of the Johns Hopkins University (JHU) Animal Care and Use Program. Experimental protocols were Approved by the JHU Animal Care and Use Committee. All cages were illuminated by fluorescent lights set to a 12-hour light-dark cycle (7am-7pm), as per U.S. Public Health Service Policy on Humane Care and Use of Laboratory Animals guidelines.