Abstract 583: Rapid release of ctDNA as a biomarker of treatment response in preclinical models of head and neck squamous cell carcinoma
Notice bibliographique
Résumé
Abstract Purpose: High-dose radiotherapy (RT) is a standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC). Despite known molecular prognostic biomarkers in HNSCC, such as the presence of human papillomavirus (HPV) within tumor tissues, RT regimens remain one-size-fits-all without any patient-specific individualization. We hypothesize that rapid release of circulating tumor DNA (ctDNA) can act as a biomarker of treatment response in HNSCC by reflecting tumor cell death in response to RT. Methods: Four HNSCC cell lines, two HPV- (Cal33, FaDu) and two HPV+ (HMS-001, 93-Vu147T), were evaluated for ctDNA release following single dose RT in vitro. Quantification of ctDNA was performed by quantitative polymerase chain reaction (qPCR) with primers amplifying the human long interspersed nuclear element 1 (hLINE1). RT-induced apoptosis was measured using a luminometric caspase 3/7 assay, and RT-induced senescence was evaluated using a fluorometric senescence associated β-galactocidase (SA-β-Gal) assay. The pan-caspase inhibitor, z-vad-fmk, was used to block RT-induced apoptosis. Subcutaneous cell-line xenografts were established in Nod-Scid-Gamma (NSG) mice, where plasma from serial blood draws was purified and quantified for ctDNA release using hLINE1 qPCR. Endpoint tumors were evaluated for mechanisms of cell death by histological staining. Results: HNSCC cell lines exhibited variable magnitude and timing of ctDNA release and apoptosis. Maximal ctDNA release occurred between 72 and 144 hours post-RT. The release of ctDNA was not correlated with HPV status nor with apoptosis occurring following RT. To further interrogate the contribution of apoptosis to ctDNA release, we treated cells with a pan-caspase inhibitor and evaluated ctDNA release and caspase activity following RT. Although caspase inhibition resulted in a near complete reduction in RT-induced caspase activity (84.0% ±8.1%), a comparatively minor reduction in ctDNA release (28.9%±8.9%) was observed. To evaluate the impact of senescence on RT-induced ctDNA release, we measured SA-β-Gal activity post-RT. The degree of senescence following RT was inversely associated with ctDNA release. In cell line xenografts, maximal ctDNA release into mouse plasma occurred 96 hours following RT. Staining patterns of endpoint tumors for caspase-3, TUNEL, p21, and Ki67 are currently under analysis. Conclusions: Our results demonstrate a robust and sensitive method for longitudinal evaluation of ctDNA release and cell death post-RT both in vitro and in vivo. Timing of ctDNA release demonstrate peaks around 72-96 hours post-RT, highlighting the potential for ctDNA to depict early response to therapy. Ongoing studies aimed at further investigating ctDNA release in association with mechanisms of cell death in vivo will help further elucidate the potential for ctDNA as a biomarker of treatment response. Citation Format: Ariana Rostami, Caberry Yu, Marco A. Di Grappa, Scott V. Bratman. Rapid release of ctDNA as a biomarker of treatment response in preclinical models of head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 583.
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 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».