PARP-1-targeted radiotherapy in mouse models of glioblastoma Journal Article

Authors: Jannetti, S. A.; Carlucci, G.; Carney, B.; Kossatz, S.; Shenker, L.; Carter, L. M.; Salinas, B.; Brand, C.; Sadique, A.; Donabedian, P. L.; Cunanan, K. M.; Gönen, M.; Ponomarev, V.; Zeglis, B. M.; Souweidane, M. M.; Lewis, J. S.; Weber, W. A.; Humm, J. L.; Reiner, T.
Article Title: PARP-1-targeted radiotherapy in mouse models of glioblastoma
Abstract: The DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is overexpressed in glioblastoma, with overall low expression in healthy brain tissue. Paired with the availability of specific small molecule inhibitors, PARP-1 is a near-ideal target to develop novel radiotherapeutics to induce DNA damage and apoptosis in cancer cells, while sparing healthy brain tissue. Methods: We synthesized an 131I-labeled PARP-1 therapeutic and investigated its pharmacology in vitro and in vivo. A subcutaneous tumor model was used to quantify retention times and therapeutic efficacy. A potential clinical scenario, intratumoral convection-enhanced delivery, was mimicked using an orthotopic glioblastoma model combined with an implanted osmotic pump system to study local administration of 131I-PARPi (PARPi is PARP inhibitor). Results: 131IPARPi is a 1(2H)-phthalazinone, similar in structure to the Food and Drug Administration-approved PARP inhibitor AZD-2281. In vitro studies have shown that 131I-PARPi and AZD-2281 share similar pharmacologic profiles. 131I-PARPi delivered 134.1 cGy/ MBq intratumoral injected activity. Doses to nontarget tissues, including liver and kidney, were significantly lower. Radiation damage and cell death in treated tumors were shown by p53 activation in U87-MG cells transfected with a p53-bioluminescent reporter. Treated mice showed significantly longer survival than mice receiving vehicle (29 vs. 22 d, P , 0.005) in a subcutaneous model. Convection-enhanced delivery demonstrated efficient retention of 131I-PARPi in orthotopic brain tumors, while quickly clearing from healthy brain tissue. Conclusion: Our results demonstrate 131IPARPi's high potential as a therapeutic and highlight PARP's relevance as a target for radionuclide therapy. Radiation plays an integral role in brain tumor therapy, and radiolabeled PARP therapeutics could ultimately lead to improvements in the standard of care. © Copyright 2018 by the Society of Nuclear Medicine and Molecular Imaging.
Keywords: 131i; parp; 131i-parpi; convection enhanced delivery (ced); radiotherapeutic
Journal Title: Journal of Nuclear Medicine
Volume: 59
Issue: 8
ISSN: 0161-5505
Publisher: Society of Nuclear Medicine  
Date Published: 2018-08-01
Start Page: 1225
End Page: 1233
Language: English
DOI: 10.2967/jnumed.117.205054
PROVIDER: scopus
PMCID: PMC6071508
PUBMED: 29572254
Notes: Article -- Export Date: 4 September 2018 -- Source: Scopus
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