Abstract A058 Response of neuroblastoma patient-derived xenografts to cyclophosphamide + topotecan enables identification of gene expression patterns associated with drug resistance
Notice bibliographique
Résumé
Abstract Neuroblastoma (NBL) is the most common extra-cranial solid tumor with <60% long-term survival in high-risk patients. Approximately 15% of high-risk NBL patients develop progressive disease (PD) during induction chemotherapy. As tumor biopsies are often not obtained at time of PD, identifying underlying genetic/genomic features that contribute to disease progression is challenging. Patient-derived xenografts (PDX) established from NBL cells in bone marrow aspirates or blood samples obtained pre-therapy and at time of PD can be phenotypically and molecularly characterized to potentially identify biomarkers predictive of treatment outcome in high-risk NBL patients. Thirty-five high-risk patient tumor, marrow, or blood samples, 16 at diagnosis (DX) and 19 at PD, were received via Children’s Oncology Group (COG) protocol ANBL00B1 and established as PDXs. PDXs were classified by response to chemotherapy (cyclophosphamide, 30mg/kg + topotecan, 0.6 mg/kg daily for 5 days every 21 days, total of 3 cycles) as non-responders (NR) and responders (R), the latter then divided into partial responders (PR) and complete responders (CR). The gene expression in the PDXs was analyzed by RNA-sequencing, and the expression profiles were analyzed by differential analysis (DEGs) via edgeR, binomial regression model, and student’s t-test to identify the marker genes for NR group. The markers were validated using real-time RT-PCR. PDX cyclo/topo response was: non-response (NR, n=13), partial response (PR, n=9), and complete response (CR, n=13). The event-free survival in all treatment groups was significantly extended relative to their control (P < 0.001). Nine of 13 (69%) of the NR PDXs were established from post-mortem PD (PD-PM) samples while nine of thirteen (69%) of the CR group were from diagnosis (DX) samples, demonstrating the clinical relevance of the PDX models. The RNA-seq data analysis identified 639 differentially expressed genes across the NR versus response groups. A regression model and t-test significance further filtered these genes to define a signature comprised of 21 genes for the NR group (P < 1.8e-12). When assessing only DX PDX models, a set of 26 genes was identified as a signature for the NR group (P < 4.1e-05). WNT signaling and Hedgehog pathways were the two most highly activated in the NR group relative to the R group. Of the 639 differentially expressed genes, we investigated nine genes that showed highly significant differential expression by RT-PCR, and seven of the nine genes tested (P < 0.05). Response of PDXs to cyclophosphamide/topotecan was greater for pretherapy (DX) PDXs than PD-PM PDXs. The gene expression signature of NR PDXs can potentially provide a biomarker to identify patients destined to have suboptimal responses to induction chemotherapy. Genes overexpressed in NR PDXs provide potential molecular targets to reverse drug resistance. In addition, the well-characterized and clinically relevant panel of PDXs will be valuable in preclinical studies of novel therapeutic approaches for high-risk neuroblastoma patients. Citation Format: Nighat Noureen, Harry May, In-Hyoung Yang, Kristyn McCoy, Jonas Nance, Diana Ixlamati-Nava, Meredith S Irwin, Michael D. Hogarty, Charles P. Reynolds, Min H. Kang. Response of neuroblastoma patient-derived xenografts to cyclophosphamide + topotecan enables identification of gene expression patterns associated with drug resistance [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 A058.
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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 | 0,000 | 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) | 0,002 | 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 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 ».