Abstract 6383: Targeting radiation-induced fibrosis: Exploring promising therapeutic avenues and innovative assessment methods
Notice bibliographique
Résumé
Abstract Introduction: Radiation therapy is a vital cancer treatment for nearly 50% of patients, yet it poses a significant challenge in the form of radiation-induced fibrosis (RF). RF affects about 60% of those undergoing radiation, leading to painful scarring from excessive collagen accumulation. In head and neck cancer patients, as an example, RF reduces tissue flexibility, causing limited neck mobility and impaired swallowing. Furthermore, approximately 30% of patients also face disease recurrence post-radiation, with RF increasing surgical complications. Our laboratory previously identified the role of reduced fatty acid oxidation in RF (Zhao et al; Nat Metab;1(1):147 2019), offering a promising avenue for future drug development. We described the potential therapeutic benefit of caffeic acid phenethyl ester (CAPE) in countering pro-fibrotic metabolic changes. Our current objective is to develop more effective lead compounds to mitigate RF. Methods: Collagen expression, utilized as a surrogate marker for fibrosis, was quantified using ELISA, Western blot analysis, and RT-qPCR. Metabolic changes were assessed by examining the expression levels of PPARG and CD36. CAPE-like analogs were derived from an in-house collection, a commercially available library, and structure-activity relationship (SAR) analyses. In vivo, RF was induced in the hindlimbs of mice through exposure to 40 Gy, followed by weekly X-ray evaluations of hindlimb angles for 16 weeks. During X-ray assessments, both hindlimbs were subjected to a 5 g weight to enable measurement of the joint angle between the femur and tibia (wherein higher acute angles were a measure of worsening fibrosis). Skin samples from irradiated and unirradiated limbs were collected for the evaluation of collagen deposition, utilizing Picro Sirius staining followed by polarized microscopy. Results: Amongst 200 newly synthesized analogs, approximately one-third successfully reduced collagen secretion in human primary dermal fibroblasts. The most promising compounds exhibited a half-maximum inhibition concentration (IC50) for collagen secretion from 1 to 5µM. They also decreased intracellular collagen production and gene expression, associated with upregulation of PPARG and CD36 transcripts. The joint angle measurements in vivo revealed three distinct phases in the development of dermal fibrosis: 1) inflammatory; 2) recovery; and 3) fibrotic phases. Conclusions: We have successfully synthesized novel and potent analogs of CAPE which were able to reduce secretion of collagen. Furthermore, a novel method for the in vivo assessment of fibrosis was also developed. This innovative approach will facilitate the detailed assessments of future compounds capable of reducing collagen deposition in vivo, thereby providing an innovative avenue to mitigate one of the most pressing late normal tissue toxicities of radiation therapy. Citation Format: Pierre-Antoine Bissey, Leonardo Massignan, Ross Mancini, Wei Shi, Justin Williams, Mark Reed, Kenneth W. Yip, Fei-Fei Liu. Targeting radiation-induced fibrosis: Exploring promising therapeutic avenues and innovative assessment methods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6383.
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 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 | 0,003 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 | 0,001 |
| 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 ».