PARP-1-targeted radiotherapy in mouse models of glioblastoma

Stephen A. Jannetti, Giuseppe Carlucci, Brandon Carney, Susanne Kossatz, Larissa Shenker, Lukas M. Carter, Beatriz Salinas, Christian Brand, Ahmad Sadique, Patrick L. Donabedian, Kristen M. Cunanan, Mithat Gönen, Vladimir Ponomarev, Brian M. Zeglis, Mark M. Souweidane, Jason S. Lewis, Wolfgang A. Weber, John L. Humm, Thomas Reiner

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish
Pages (from-to)1225-1233
Number of pages9
JournalJournal of Nuclear Medicine
Volume59
Issue number8
DOIs
StatePublished - 1 Aug 2018
Externally publishedYes

Keywords

  • 131I
  • 131I-PARPi
  • Convection enhanced delivery (CED)
  • PARP
  • Radiotherapeutic

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