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 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 September 2018 -- Source: Scopus |
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