Abstract B33: PARP-dependent co-modulation of DNA repair and microglial activity as a dual-pronged anti-glioblastoma treatment strategy
Notice bibliographique
Résumé
Abstract Introduction: Glioblastoma multiforme (GBM) is an aggressive form of brain cancer with poor treatment outcomes and prognoses. Treatment usually consists of surgery, radiation and chemotherapy, which often result in severe systemic side effects frequently accompanied by tumor recurrence of highly radioresistant tumor cell populations. PARP-1 is a nuclear enzyme crucial for DNA damage repair (DDR) response. PARP-1 inhibition is a highly studied adjuvant to many anti-cancer treatment strategies as this arrests DNA damage repair thus enhancing the efficacy of conventional chemoradiotherapy at lower doses. However, PARP inhibition also promotes anti-inflammatory responses. Cancer cells suppress the immune cells ability to recognize and eliminate the tumor and promote their release of cancer-supporting growth factors and promote angiogenesis. Microglia the immune cells of the brain, normally protect the brain from pathogens and help in tissue recovery, but when associated with GBM cells, microglia obtain anti-inflammatory state that can promote tumor growth. We are developing a novel bimodal immunotherapeutic/DNA repair suppressive approach to treating GBM through modulation of microglial PARP-1 activity while concurrently sensitizing GBM to DNA damaging therapeutics. We hypothesize that while PARP-1 inhibition can enhance efficacy of chemoradiotherapy it might further suppress microglial ability to promote tumor elimination. Furthermore PARP-1 inhibitors' efficacy in preventing DNA repair is partially linked to their ability to trap PARP-1 at DNA break-site, which might be detrimental for the viability of non-cancerous brain cells. Objectives: 1) to establish the effects of PARP-1 inhibition alone, and in combination with targeted microglial PARP-1 activation, on microglial ability to eliminate glioblastoma cells in vitro (tumor cells vs. healthy glial cells). 2) to identify how microglial PARP-1 modulation (on/off) impacts glioblastoma elimination in vivo (tumor vs. brain). Methods: We will use GBM cells co-cultured with primary microglial cells in the presence of PARP inhibitors and observe their effect on the proliferation and viability of GBM cells. Efficacy of PARP-DNA trapping and corresponding DNA damage repair activity utilizing a variety of PARP inhibitors will be tested by specific biochemical and genotoxicity assays which directly quantify the degree of PARP-trapping in the glial cells and their impact on tumor cell genotoxcity. These studies take advantage of newly-developed and unique high-throughput DNA damage repair assays that we have been optimized to determine potential synergy of PARP-inhibitors with existing chemotherapeutic agents. Results: DNA damage assays (gamma H2AX foci and alkaline comet analysis) show that co-treatment of GBM cells (U87 and U251) with the PARP-inhibitor Olaparib and the chemotherapeutic agent Camptothecin (CPT) significantly increased the level of DNA damage when compared to CPT treatment alone. In the co-culture experiments, microglia enhanced CPT-induced GBM cell death when treated with Olaparib at 50-100 fold lower doses. Real time co-culture experiments also showed that Olaparib does not jeopardize microglial ability to actively phagocytize GBM cells. Conclusion: Preliminary results show that Olaparib is effective in sensitizing GBM cells to chemotherapy while microglia appear to enhance this effect. Further studies linking this combination therapy with microglia-mediated GBM elimination will help to elucidate the mechanism of this bimodal effect. This study emphasizes the importance of: (1) identifying novel effects of PARP inhibition on microglia in association with GBM and (2) the importance of developing microglia-mediated immunotherapeutic intervention to overcome the limitations of current therapies to significantly improve patient outcome. Citation Format: Asha Sinha, Sachin Katyal, Tiina Kauppinen. PARP-dependent co-modulation of DNA repair and microglial activity as a dual-pronged anti-glioblastoma treatment strategy [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B33.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».