Abstract B31: Poly(ADP-ribose) Polymerase 1 as a novel target for alpha-particle therapy in high-risk neuroblastoma
Notice bibliographique
Résumé
Abstract Introduction: Poly(ADP-ribose) Polymerase 1 (PARP-1) is the second most abundant nuclear protein next to histones and offers a unique target for the delivery of alpha emitting radionuclides directly to chromatin maximizing radiobiological effects. Alpha emitting radionuclides decay through the emission of a high linear energy transfer alpha particle that travels only 50-70 µM. This results in dense ionizations over the alpha particle track length, causing high levels of DNA double strand breaks. High-risk neuroblastoma is a deadly pediatric malignancy that overexpresses PARP-1 and approximately 80% of patients succumb to their disease. By utilizing the overexpression of PARP-1 we aim to selectively target high-risk neuroblastomas for the delivery of alpha particles to induce irreparable DNA damage and subsequent cell death. Methods: Astatine-211 was produced on a JSW BC3015 cyclotron at 28.5 MeV via the Bi-209(α,2n)At-211 nuclear reaction. Astatine-211 was isolated by dry distillation and radiochemically functionalized onto a small molecule PARP inhibitor to afford 211At-MM4. Using a panel of neuroblastoma cell lines, the pharmacology and cytotoxicity of 211At-MM4 was evaluated in vitro. Next, protein analysis was performed by Western to evaluate expression of classical and alternative non-homologous end joining proteins. In addition, PARP-1 expression and DNA damage were assessed in response to therapy. Furthermore, in vivo therapy studies with PET/CT imaging of PARP-1 were performed to assess therapeutic potential and predictive capabilities of companion diagnostics. Results: IMR-05, SK-N-SH, and NLF were the most sensitive cell lines evaluated and Be-2-c was the most resistant cell line. All cell lines evaluated were high-risk neuroblastomas and baseline Western protein analysis did not reveal specific pathway dependence for classical or alternative non-homologous end joining defined by protein expression. Response to therapy showed significant increases in DNA damage measured by gH2AX. Interestingly PARP-1 expression was upregulated post therapy in the resistant cell line Be-2-c. IMR-05 was the most sensitive cell line in vitro and was translated to in vivo models where therapeutic efficacy was shown. PET/CT imaging of PARP-1 post therapy showed low tumor uptake and was indicative of response. Conclusion: 211At-MM4 is a small molecule PARP inhibitor functionalized with an alpha emitting radionuclide astatine-211 that can effectively deliver alpha-particles to the nucleus of cancer cells. The neuroblastoma cell lines evaluated showed differential sensitivities and in vitro results translated into in vivo models. Furthermore we have characterized a novel therapy for high-risk neuroblastoma and aim for future clinical translation. Citation Format: Mehran Makvandi, Catherine Hou, Kuiying Xu, Redmond-Craig Anderson, Samuel Ander-Effron, Robert H. Mach, John M. Maris, Daniel A. Pryma. Poly(ADP-ribose) Polymerase 1 as a novel target for alpha-particle therapy in high-risk neuroblastoma [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 B31.
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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 | 0,001 |
| 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 | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| 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 ».