PARP1-Targeted Radiotherapy in Mouse Models of Glioblastoma.

PARP1-Targeted Radiotherapy in Mouse Models of Glioblastoma.

J Nucl Med. 2018 Mar 23;:

Authors: Jannetti SA, Carlucci G, Carney B, Kossatz S, Shenker L, Carter LM, Salinas B, Brand C, Sadique A, Donabedian PL, Cunanan KM, Gönen M, Ponomarev V, Zeglis BM, Souweidane MM, Lewis JS, Weber WA, Humm JL, Reiner T

Abstract
The DNA repair enzyme PARP1 is over-expressed in glioblastoma, with overall low expression in healthy brain tissue. Paired with the availability of specific molecularly targeted small molecules for this biomarker, PARP1 is a near-ideal target for novel radiotherapeutics. A successful PARP1-targeted radiotherapeutic would induce DNA damage and apoptosis in cancer cells, while sparing healthy brain tissue. We synthesized a 131I-labeled poly(ADP-ribose) polymerase 1 (PARP1) therapeutic and investigated its pharmacology using in vitro and in vivo methodologies. A subcutaneous mouse model was used to quantify retention times and therapeutic efficacy. A potential clinical scenario, intratumoral convection-enhanced delivery (CED), was mimicked using an orthotopic glioblastoma model combined with an implanted osmotic pump system to study local administration of [131I]PARPi. [131I]PARPi is a 1(2H)-phthalazinone, similar in structure to the FDA-approved PARP inhibitor Olaparib (Lynparza, Astra-Zeneca). In vitro studies have shown that [131I]PARPi and Olaparib share similar pharmacologic profiles. [131I]PARPi delivers 134.1 cGy/MBq intratumoral injected activity; doses to non-target tissues, including liver and kidney, were significantly lower. Radiation damage and cell death could be shown by p53 activation via bioluminescence imaging in U87 MG cells transfected with a p53-bioluminescent reporter in treated tumors. Treated mice had significantly longer survival than mice receiving only vehicle (29 vs. 22 days, P < 0.005) in a subcutaneous model. CED demonstrated efficient retention of [131I]PARPi in orthotopic brain tumors, while quickly clearing from healthy brain tissue. We validated the novel PARP1-targeted radiotherapeutic [131I]PARPi, studying its performance in mouse models. 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.

PMID: 29572254 [PubMed - as supplied by publisher]

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