Abstract B016: Targeting the angiotensin receptor in cancer-associated fibroblasts improves tumour perfusion, oxygenation, and radiotherapy response
Notice bibliographique
Résumé
Abstract The solid tumor microenvironment is a key determinant of successful cancer therapy, with hypoxic tumor cells known to contribute to poor therapeutic outcome after radiation therapy, chemotherapy, and surgery. Several targeted therapies have been developed against hypoxic tumor cells that have shown promise in combination with radiation therapy in pre-clinical models and early phase clinical trials, although the difficulty inherent in targeting hypoxic cells has limited the overall efficacy of this approach. Our recent data suggest that hypoxia can develop in solid tumors due to the activity of sub-populations of cancer-associated fibroblasts (CAFs), and that therapeutically targeting CAF activation can restrict the development of tumor hypoxia and prime tumors to respond to radiation therapy. Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are anti-hypertensive agents that inhibit the activity of the signaling peptide angiotensin II derived from the renin-angiotensin system. ARBs can also exhibit anti-fibrotic activity by blocking the AT1R expressed on myofibroblasts in various tissues. We recently found that the ARB telmisartan inhibits the deposition of collagen I in solid tumors, increasing net tumor perfusion and stabilizing microregional tumor blood flow. Collagen I can be produced by CAFs, although recent clinical data have identified multiple, functionally-diverse CAF subsets in breast and ovarian tumors. To understand how ARBs affect the solid tumor microenvironment, we wanted to determine how the ARB telmisartan influences the activity of CAF subsets and whether telmisartan-associated changes in perfusion impact hypoxia and radiation response in solid tumors. We identified several murine CAF subsets that could be discriminated by cell surface marker expression across a panel of seven tumor xenograft lines. Using single cell RNAseq of cells isolated from tumors with or without ARB treatment, we found that telmisartan altered the transcriptome of CAF subsets and inhibited CAF activation. In tumors containing myofibroblast-like CAFs, telmisartan decreased collagen deposition and eliminated ‘acute’ hypoxia that can be caused by unstable microregional perfusion. Telmisartan-treated tumors also had improved response to ionizing radiation therapy. Taken together, our data indicate that CAFs contribute to tumor hypoxia and radiation resistance of solid tumors in an AT1R-dependent manner. Using a retrospective cohort of over 1,100 oropharyngeal cancer patients, we also found that patients taking ARBs for hypertension had dramatically improved therapeutic outcomes after radiation therapy. Our work indicates that CAFs contribute to the development of hypoxia in solid tumors and suggests that angiotensin receptor blockers represent a novel targeted therapy to inhibit CAF activity, modify the solid tumor microenvironment, reduce tumor hypoxia, and improve radiation response. Citation Format: Che-Min Lee, Brennan J. Wadsworth, Rachel A. Cederberg, Zi Han Li, Kiersten N. Thomas, Meredith Clark, Rocky Shi, Michael Hall, Nikita Telkar, Ryan Urban, Wan L. Lam, Sarah N. Hamilton, Kevin L. Bennewith. Targeting the angiotensin receptor in cancer-associated fibroblasts improves tumour perfusion, oxygenation, and radiotherapy response. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B016.
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 | 0,000 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 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 ».