Abstract A065 Immunoliposome for Ewing sarcoma
Notice bibliographique
Résumé
Abstract Background. Metastatic and recurrent Ewing sarcoma (EWS) poses significant mortality risk in children and adolescents. Advances in precision medicine can help to mitigate dismal outcomes by designing targeted delivery of drugs for more effective eradication of cancer cells. This study aimed to identify a rationalized combination of antibody-covered immunoliposomes (IL) loaded with a small molecule against EWS. CD99 antigen is typically expressed on EWS cells and is used for diagnostics. However, CD99 is also expressed in normal tissues, and, if used for a targeted nanoparticle, its payload must be more damaging to EWS than normal cells. FDA-approved poly ADP ribose polymerase (PARP) inhibitors may present such an opportunity, since EWS is treated with DNA-damaging agents and PARP inhibition may enhance cell apoptosis. Methods. R2 genomics analysis platform (http://r2.amc.nl) was used to explore the potential of CD99-covered and PARP inhibitor loaded IL. Seven different databases were used for differential expression of CD99 and PARP1, two EWS databases and five normal tissue databases (B cells, endothelial cells, hematopoietic, lymphocytes, and various normal tissues). Kaplan-Meier analysis was conducted for prognostic significance of PARP1 overexpression in one of the EWS datasets containing survival data in R2. Lastly, comparative side effect profiling of variable PARP inhibitors is discussed and was utilized for selection of a candidate molecule for the presumed IL. Results. In two EWS datasets (Savola, n=117 & Surdez, n=79) CD99 expression was 2-3 times higher than 5 sets of normal tissues (n=637). Endothelial compartment has twice-higher CD99 compared to other normal tissues but ∼1.5 times lower CD99 and PARP1 than EWS. Recurrent/metastatic EWS has more PARP1 than primary tumors as seen in Savola dataset, p=0.02 (anova). Higher PARP1 expression was associated with worse event-free (EFS) and overall survivals (OS) further validating potential role of PARP inhibition in EWS. Ten-year survivals respectively for low versus high PARP1 expression were 36% and 14% for EFS (p=0.016), and 50% and 7% for OS (p<0.001). Normal hematopoietic/B-cell compartments have ≥2-times higher PARP1 than other datasets; therefore, for IL payload it is crucial to select an inhibitor with less lymphotoxicity. Discussion. Small molecule niraparib causes less lymphopenia compared to other PARP inhibitors, thus it would be a preferred candidate for the suggested nanoparticle. It has a molecular weight of 320g/mol, which should allow an ample amount to be packaged into a 100 nm IL. This size with PEG-linked attachment of monoclonal antibodies (mAbs) against CD99 may provide vascular permeability and tumor tropism as was seen in preclinical work of other ILs. Conclusion. ILs covered with PEG-linked anti-CD99 mAbs and loaded with niraparib may be developed as an adjuvant therapy for metastatic and recurrent EWS. Extensive preclinical testing will be required to ensure acceptable hematopoietic side effects and endothelial damage as seen with other targeted therapies. Citation Format: Daniel E. Panosyan, William S Panosyan, Joseph L. Lasky III. Immunoliposome for Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A065.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,001 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».