Abstract 3434: Selective glucocorticoid receptor modulation reveals a new role for CLEC10A in patients with solid tumors
Notice bibliographique
Résumé
Abstract Selective glucocorticoid receptor (GR) modulators (SGRMs) represent a clinically validated mechanism of enhancing chemosensitivity and ameliorating the sequelae of hypercortisolism. While GRs reportedly control the expression of up to 20% of the human genome, specific targets of systemic GR antagonism in humans have yet to be identified. To address this question, we established a robust NanoString assay to measure candidate GR target genes in human blood and assessed them before and after therapy with the oral SGRM relacorilant, which selectively antagonizes the GR. In a randomized, controlled phase 2 study in patients with recurrent, platinum-resistant ovarian cancer (NCT03776812), gene changes were assessed in 139 patients after treatment with relacorilant + nab-paclitaxel (NP) or NP alone. Using cross-validated random forest methods, a gene panel that accurately identified patients who had received relacorilant was established (ROC AUC 0.945 +/- 0.038). In 13 patients who crossed over from NP alone to relacorilant + NP, the genes in the panel were modified only after crossover (paired t-test P=0.0003), validating the gene panel’s ability to detect GR activity. The 4 most induced (LILRB4, FPR3, CLEC10A, CCR2) and 4 most suppressed (CDKN1C, TNFRSF17, BRIP1, PDK1) genes by relacorilant + NP vs. NP alone were selected and shown to be reliable indicators of GR activity across clinical studies in patients with pancreatic, prostate, and other solid tumors (NCT04329949, NCT03674814, NCT02762981), independent of concomitant medications or other confounders. CLEC10A (C-type lectin domain containing 10A) was identified as a particularly sensitive marker of GR activity as its expression was strongly suppressed by the GR agonist prednisone in healthy volunteers (paired t-test P<0.00010, NCT03335956) and strongly induced by relacorilant in patients with solid tumors (paired t-test P<0.00010). CLEC10A induction in blood by relacorilant was associated with longer overall survival in patients with ovarian cancer treated with relacorilant + NP (HR=0.39, Cox PH P=0.0135). High baseline tumor CLEC10A expression was also associated with longer overall survival in a large tumor ‘omics’ database (N=1656 ovarian tumors; HR 0.8, log-rank P=0.0008). CLEC10A and the genes correlated with its expression were found to be primarily expressed by a specific subset of dendritic cells, supporting previous reports that GR agonism can suppress dendritic cells. This analysis of CLEC10A and other identified GR target genes confirmed that systemic GR activity in patients with a range of solid tumors can be modulated pharmacologically, indicates that GR modulation may be associated with survival in patients with ovarian cancer, and provides new insights into the systemic functions of the GR in humans. Citation Format: Nicoletta Colombo, Toon Van Gorp, Ursula A. Matulonis, Ana Oaknin, Rachel N. Grisham, Diane Provencher, Gini F. Fleming, Alexander B. Olawaiye, Erkut H. Borazanci, Russell Z. Szmulewitz, Subhagya A. Wadekar, Grace Mann, Hazel J. Hunt, Andrew E. Greenstein, Domenica Lorusso. Selective glucocorticoid receptor modulation reveals a new role for CLEC10A in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3434.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,002 |
| 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 ».