|PARP-1-Targeted Radiotherapy in Mouse Models of Glioblastoma.
|Year of Publication
|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
|J Nucl Med
|Animals, Cell Line, Tumor, Disease Models, Animal, Female, Glioblastoma, Mice, Molecular Targeted Therapy, Poly (ADP-Ribose) Polymerase-1, Radiometry, Single Photon Emission Computed Tomography Computed Tomography, Tumor Suppressor Protein p53
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. We synthesized an I-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 I-PARPi (PARPi is PARP inhibitor). I-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 I-PARPi and AZD-2281 share similar pharmacologic profiles. I-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, < 0.005) in a subcutaneous model. Convection-enhanced delivery demonstrated efficient retention of I-PARPi in orthotopic brain tumors, while quickly clearing from healthy brain tissue. Our results demonstrate I-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.
|J Nucl Med
|PubMed Central ID
|P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA204441 / CA / NCI NIH HHS / United States
R21 CA191679 / CA / NCI NIH HHS / United States