PT  - JOURNAL ARTICLE
AU  - Stephen A. Jannetti
AU  - Giuseppe Carlucci
AU  - Brandon Carney
AU  - Susanne Kossatz
AU  - Larissa Shenker
AU  - Lukas M. Carter
AU  - Beatriz Salinas
AU  - Christian Brand
AU  - Ahmad Sadique
AU  - Patrick L. Donabedian
AU  - Kristen M. Cunanan
AU  - Mithat Gönen
AU  - Vladimir Ponomarev
AU  - Brian M. Zeglis
AU  - Mark M. Souweidane
AU  - Jason S. Lewis
AU  - Wolfgang A. Weber
AU  - John L. Humm
AU  - Thomas Reiner
TI  - PARP-1–Targeted Radiotherapy in Mouse Models of Glioblastoma
AID  - 10.2967/jnumed.117.205054
DP  - 2018 Aug 01
TA  - Journal of Nuclear Medicine
PG  - 1225--1233
VI  - 59
IP  - 8
4099  - http://jnm.snmjournals.org/content/59/8/1225.short
4100  - http://jnm.snmjournals.org/content/59/8/1225.full
SO  - J Nucl Med2018 Aug 01; 59
AB  - 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.