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Title:

PARP-1-Targeted Radiotherapy in Mouse Models of Glioblastoma.

Document type:
Journal Article
Author(s):
Jannetti, Stephen A; Carlucci, Giuseppe; Carney, Brandon; Kossatz, Susanne; Shenker, Larissa; Carter, Lukas M; Salinas, Beatriz; Brand, Christian; Sadique, Ahmad; Donabedian, Patrick L; Cunanan, Kristen M; Gonen, Mithat; Ponomarev, Vladimir; Zeglis, Brian M; Souweidane, Mark M; Lewis, Jason S; Weber, Wolfgang A; Humm, John L; Reiner, Thomas
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:131I-PARPi 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 131I-PARPi'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.
Journal title abbreviation:
J Nucl Med
Year:
2018
Journal volume:
59
Journal issue:
8
Pages contribution:
1225-1233
Fulltext / DOI:
doi:10.2967/jnumed.117.205054
Pubmed ID:
http://view.ncbi.nlm.nih.gov/pubmed/29572254
Print-ISSN:
0161-5505
TUM Institution:
Klinik und Poliklinik für Nuklearmedizin
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