Dataset Information

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

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.

SUBMITTER: Jannetti SA

PROVIDER: S-EPMC6071508 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Jannetti Stephen A SA Carlucci Giuseppe G Carney Brandon B Kossatz Susanne S Shenker Larissa L Carter Lukas M LM Salinas Beatriz B Brand Christian C Sadique Ahmad A Donabedian Patrick L PL Cunanan Kristen M KM Gönen Mithat M Ponomarev Vladimir V Zeglis Brian M BM Souweidane Mark M MM Lewis Jason S JS Weber Wolfgang A WA Humm John L JL Reiner Thomas T

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20180323 8

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. <b>Methods:</b> We synthesized an <sup>131</sup>I-labeled PARP-1 therapeutic and investigated its pharmacology in vitro and in vivo ...[more]

PMID: 29572254

Similar Datasets

Project description:Despite Auger electrons being highly appealing due to their short-range and high linear energy transfer to surrounding tissues, the progress in the field has been limited due to the challenge in delivering a therapeutic dose within the close proximity of cancer cell's DNA. Here, we demonstrate that the PARP inhibitor 123I-MAPi is a viable agent for the systemic administration and treatment of p53 mutant cancers. Significantly, minimal off-site toxicity was observed in mice administered with up to 74 MBq of 127I-PARPi. Taken together, these results lay the foundation for future clinical evaluation and broader preclinical investigations. By harnessing the scaffold of the PARP inhibitor Olaparib, we were able to deliver therapeutic levels of Auger radiation to the site of human colorectal cancer xenograft tumors after systemic administration. In-depth toxicity studies analyzed blood chemistry levels and markers associated with specific organ toxicity. Finally, p53+/+ and p53-/- human colorectal cancer cell lines were evaluated for the ability of 123I-MAPi to induce tumor growth delay. Toxicity studies demonstrate that both 123I-MAPi and its stable isotopologue, 127I-PARPi, have no significant off-site toxicity when administered systemically. Analysis following 123I-MAPi treatment confirmed its ability to induce DNA damage at the site of xenograft tumors when administered systemically. Finally, we demonstrate that 123I-MAPi generates a therapeutic response in p53-/-, but not p53+/+, subcutaneous xenograft tumors in mouse models. Taken together, these results represent the first example of a PARP Auger theranostic agent capable of delivering a therapeutic dose to xenograft human colorectal cancer tumors upon systemic administration without causing significant toxicity to surrounding mouse organs. Moreover, it suggests that a PARP Auger theranostic can act as a targeted therapeutic for cancers with mutated p53 pathways. This landmark goal paves the way for clinical evaluation of 123I-MAPi for pan cancer therapeutics.

Project description:Abstract Paediatric high grade glioma (pHGG) are defined by recurrent mutations in H3 histones, as well as frequent alterations in the SWI/SNF chromatin remodelling gene ATRX (α-thalassemia mental retardation X-linked), although the precise role of ATRX in tumorigenesis remains unclear. We sought to explore this using genomic analysis of patient samples, CRISPR-Cas9 engineered isogenic ATRX knockout (KO) cell lines and primary-patient-derived cultures. In combined retrospective and prospective cohorts of pHGG samples, we found ATRX mutations in 95/510 (18.6%) cases (27% hemispheric glioblastoma, 13% diffuse midline glioma), with the majority of truncating mutations found in the ADD domain, and missense mutations almost exclusively in the helicase domain. ATRX mutations commonly co-segregate with H3.3G34 and TP53 mutations, and define a subgroup of patients with a longer overall survival, though with a greater number of somatic mutations and copy number alterations than wild-type cases. CRISPR/Cas9-mediated ATRX KO targeting the ADD domain in TP53 mutant paediatric glioblastoma cells lead to loss of imprinting at the H19 locus in concert with upregulation of a pro-invasive transcriptional programme, though a slower rate of orthotopic tumour growth in vivo. ATRX deficient cells showed an abrogated DNA damage response, with prolonged accumulation of gH2AX foci after irradiation, and an increased dependency on PARP1 through persistent parylation and stalled replication forks. Screening ATRX-deficient isogenics and patient-derived cells against a library of >400 chemotherapeutics and small molecules identified a specific dependency for ATRX loss and sensitivity to distinct PARP inhibitor chemotypes, including catalytic inhibitors (olaparib, rucaparib), and PARP trappers (talazoparib). ATRX deficiency further conferred an enhanced radiosensitization of olaparib in vitro and a prolonged survival of mice treated with combined PARP inhibition and radiotherapy in vivo. These data suggest a synthetic lethality for PARP inhibitors in ATRX-deficient pHGG, and may represent a novel therapeutic strategy for these highly aggressive tumours.

Project description:ObjectiveTo investigate the efficacy and mechanism of ultrasound-targeted microbubble destruction (UTMD) combined with radiotherapy (XRT) on glioblastoma.MethodsThe enhanced radiosensitization by UTMD was assessed through colony formation and cell apoptosis in Human glioblastoma cells (U87MG). Subcutaneous transplantation tumors in 24 nude mice implanted with U87MG cells were randomly assigned to 4 different treatment groups (Control, UTMD, XRT, and UTMD + XRT) based on tumor sizes (100-300 mm3). Tumor growth was observed for 10 days after treatment, and then histopathology stains (HE, CD34, and γH2AX) were applied to the tumor samples. A TUNEL staining experiment was applied to detect the apoptosis rate of mice tumor samples. Meanwhile, tissue proteins were extracted from animal specimens, and the expressions of dsDNA break repair-related proteins from animal specimens were examined by the western blot.ResultsWhen the radiotherapy dose was 4 Gy, the colony formation rate of U87MG cells in the UTMD + XRT group was 32 ± 8%, lower than the XRT group (54 ± 14%, p < 0.01). The early apoptotic rate of the UTMD + XRT group was 21.1 ± 3% at 48 h, higher than that of the XRT group (15.2 ± 4%). The tumor growth curve indicated that the tumor growth was inhibited in the UTMD + XRT group compared with other groups during 10 days of observation. In TUNEL experiment, the apoptotic cells of the UTMD + XRT group were higher than that of the XRT group (p < 0.05). The UTMD + XRT group had the lowest MVD value, but was not significantly different from other groups (p > 0.05). In addition, γH2AX increased due to the addition of UTMD to radiotherapy compared to XRT in immunohistochemistry (p < 0.05).ConclusionsOur study clearly demonstrated the enhanced destructive effect of UTMD combined with 4 Gy radiotherapy on glioblastoma. This could be partly achieved by the increased ability of DNA damage of tumor cells.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets