<i>PARP1</i>expression and its correlation with survival is tumour molecular subtype dependent in glioblastoma

Murnyák, Balázs; Kouhsari, Mahan C.; Hershkovitch, Rotem; Kálmán, Bernadette; Markó-Varga, György; Klekner, Álmos; Hortobágyi, Tibor

doi:10.18632/oncotarget.18013

Cited by 51 publications

(37 citation statements)

References 43 publications

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“…2 ). This finding is consistent with studies in pediatric diffuse intrinsic pontine glioma [ 41 ] and adult glioblastoma [ 42 ], both of which found enhanced PARP1 expression in clinical samples of human brain tumors.…”

Section: Discussionsupporting

confidence: 92%

Discriminating radiation injury from recurrent tumor with [18F]PARPi and amino acid PET in mouse models

et al. 2018

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BackgroundRadiation injury can be indistinguishable from recurrent tumor on standard imaging. Current protocols for this differential diagnosis require one or more follow-up imaging studies, long dynamic acquisitions, or complex image post-processing; despite much research, the inability to confidently distinguish between these two entities continues to pose a significant dilemma for the treating clinician. Using mouse models of both glioblastoma and radiation necrosis, we tested the potential of poly(ADP-ribose) polymerase (PARP)-targeted PET imaging with [18F]PARPi to better discriminate radiation injury from tumor.ResultsIn mice with experimental radiation necrosis, lesion uptake on [18F]PARPi-PET was similar to contralateral uptake (1.02 ± 0.26 lesion/contralateral %IA/ccmax ratio), while [18F]FET-PET clearly delineated the contrast-enhancing region on MR (2.12 ± 0.16 lesion/contralateral %IA/ccmax ratio). In mice with focal intracranial U251 xenografts, tumor visualization on PARPi-PET was superior to FET-PET, and lesion-to-contralateral activity ratios (max/max, p = 0.034) were higher on PARPi-PET than on FET-PET.ConclusionsA murine model of radiation necrosis does not demonstrate [18F]PARPi avidity, and [18F]PARPi-PET is better than [18F]FET-PET in distinguishing radiation injury from brain tumor. [18F]PARPi-PET can be used for discrimination between recurrent tumor and radiation injury within a single, static imaging session, which may be of value to resolve a common dilemma in neuro-oncology.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0399-z) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Discriminating radiation injury from recurrent tumor with [18F]PARPi and amino acid PET in mouse models

et al. 2018

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“…PARP1 is ultimately essential for DNA repair during TMZ-based treatment and radiation therapy (Figure 3) (83). PARP1 expression is associated with TP53 and ataxia telangiectasia—Rad3 related kinase (ATR) mutations (84). GSCs display elevated basal levels of activated ATR and CHK1 along with increased replication stress (RS) expression markers including foci marked with the single-stranded DNA binding protein, replication protein A, DNA damage markers γH2AX and 53BP1 (82).…”

Section: Replication Stress: Role Of Parp Proteins In Glioma Progressionmentioning

confidence: 99%

NAMPT as a Dedifferentiation-Inducer Gene: NAD+ as Core Axis for Glioma Cancer Stem-Like Cells Maintenance

et al. 2019

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Glioma Cancer Stem-Like Cells (GSCs) are a small subset of CD133 + cells with self-renewal properties and capable of initiating new tumors contributing to Glioma progression, maintenance, hierarchy, and complexity. GSCs are highly resistant to chemo and radiotherapy. These cells are believed to be responsible for tumor relapses and patients' fatal outcome after developing a recurrent Glioblastoma (GBM) or High Grade Glioma (HGG). GSCs are cells under replicative stress with high demands on NAD + supply to repair DNA, maintain self-renewal capacity and to induce tumor plasticity. NAD + feeds Poly-ADP polymerases (PARP) and NAD + -dependent deacetylases (SIRTUINS) contributing to GSC phenotype. This energetic core axis is mainly controlled by the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT), an important oncogene contributing to tumor dedifferentiation. Targeting GSCs depicts a new frontier in Glioma therapy; hence NAMPT could represent a key regulator for GSCs maintenance. Its inhibition may attenuate GSCs properties by decreasing NAD + supply, consequently contributing to a better outcome together with current therapies for Glioma control.

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“…PARP-1 expression was reported in the nucleoli of neurons, oligodentritic cells, and astrocytes as well as the Purkinje cell layer in the cerebellum and the dentate gyrus (10). Nevertheless, it has been shown that malignant glial growths have elevated PARP-1 expression compared with healthy pediatric and adult brain tissue (11), forming an ideal foundation for CED-based therapeutics. Similarly important, PARP inhibitors not only quickly distribute and bind within PARP-expressing cells, but also simultaneously washout effectively from healthy tissues, resulting in high target-to-background contrast (10,12), potentially providing a large treatment window for CED therapy (7).…”

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confidence: 99%

PARP-1–Targeted Radiotherapy in Mouse Models of Glioblastoma

et al. 2018

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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 anI-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 forradionuclide therapy. Radiation plays an integral role in brain tumor therapy, and radiolabeled PARP therapeutics could ultimately lead to improvements in the standard of care.

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PARP1expression and its correlation with survival is tumour molecular subtype dependent in glioblastoma

Cited by 51 publications

References 43 publications

Discriminating radiation injury from recurrent tumor with [18F]PARPi and amino acid PET in mouse models

Discriminating radiation injury from recurrent tumor with [18F]PARPi and amino acid PET in mouse models

NAMPT as a Dedifferentiation-Inducer Gene: NAD+ as Core Axis for Glioma Cancer Stem-Like Cells Maintenance

PARP-1–Targeted Radiotherapy in Mouse Models of Glioblastoma

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