FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4362594103> ?p ?o ?g. }

• W4362594103 endingPage "3440" @default.
• W4362594103 startingPage "3440" @default.
• W4362594103 abstract "Abstract Introduction: Estrogen receptor gene (ESR1) drives approximately 70-80% of breast cancer cases, which are primarily treated with endocrine therapies. Mutations in the ESR1 exclusively occur in the ligand binding domain (LBD) and are significantly enriched following endocrine therapy. These mutations retain the estrogen receptor (ER) expression thus conferring ligand-independent growth, which is a paramount contributor to endocrine therapy resistant disease. Worse progression-free survival is consistently associated with ESR1 mutation status; therefore, there is an unmet need for therapies against these mutations. To this end, we recently developed TX-245, a bis-benzamide molecule that hampers the function of the two most common ESR1 mutations - Y537S and D538G. Methods: TX-245 was evaluated in vitro using MTT cell proliferation assay and colony formation assay carried out in multiple ER+ breast cancer cells harboring wild type (WT) ESR1 or mutant (MT) ESR1. Approaches such as tumor spheroid cultures were also implemented to study the effect of TX-245 compared to selected SERDs/SERMs via CellTiter-Glo 3D viability assay. Mechanistic insights were obtained performing TR-FRET assay, fluorescence polarization assay, RNA-seq, ChIP-seq, western blot, and qRT-PCR. The therapeutic efficacy in vivo was evaluated using cell xenografts, patient derived xenografts (PDX), patient derived explants (PDE), and metastatic mouse models of MT-ER breast cancer. Results: TX-245 demonstrated greater anti-proliferative dose-dependent activity in models harboring WT and MT ESR1, including those resistant to fulvestrant and tamoxifen, when compared to other SERDs/SERMs. RNAseq data suggests that TX-245 dramatically alters the transcription of ERα-regulated genes, with repression of canonical estradiol-upregulated and induction of estradiol-repressed genes. TX-245 was able to antagonize ER-chromatin interaction and ER-transcriptional signaling in breast cancer cells driven by ESR1 mutation. TX-245 treatment downregulated ER protein expression and decreased expression of ER targeted genes (i.e., GREB and PGR) in multiple ER+ cell lines. TX-245 treatment as a single agent or in combination with palbociclib resulted in tumor regression in xenografts expressing WT, Y537S or D538G ESR1 mutation. PDX and PDE models consistently exhibited substantial tumor growth inhibition as well as decreased proliferation (Ki67 staining). Metastases studies using intracardiac and intratibial injection demonstrated that TX-245 inhibited the progression of established metastatic niches in mice injected with Y537S or D538G ER+ breast cancer cells. Conclusion: Our results indicate that TX-245 inhibits cell proliferation in cell lines that express WT or mutant ESR1, induce ER degradation, suppress ER-mediated signaling and reduce tumor burden in mouse models. These studies highlight the utility of TX-245 in targeting mutations in the ER-LBD. Citation Format: Karla Parra, Suryavathi Viswanadhapalli, Tanner Reese, Xihui Liu, JunHao Liu, Zexuan Liu, Tae-Kyung Lee, Chia Yuan Chen, Kara Kassees, Jung-Mo Ahn, Ratna Vadlamudi, Ganesh Raj, Carlos Roggero. Targeting the mutant estrogen receptor in metastatic breast cancer [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 3440." @default.
• W4362594103 created "2023-04-06" @default.
• W4362594103 creator A5003178040 @default.
• W4362594103 creator A5023748431 @default.
• W4362594103 creator A5027234036 @default.
• W4362594103 creator A5043867874 @default.
• W4362594103 creator A5045699506 @default.
• W4362594103 creator A5053069471 @default.
• W4362594103 creator A5054932703 @default.
• W4362594103 creator A5056560382 @default.
• W4362594103 creator A5060097531 @default.
• W4362594103 creator A5066584293 @default.
• W4362594103 creator A5072528156 @default.
• W4362594103 creator A5081196478 @default.
• W4362594103 creator A5090010000 @default.
• W4362594103 date "2023-04-04" @default.
• W4362594103 modified "2023-09-30" @default.
• W4362594103 title "Abstract 3440: Targeting the mutant estrogen receptor in metastatic breast cancer" @default.
• W4362594103 doi "https://doi.org/10.1158/1538-7445.am2023-3440" @default.
• W4362594103 hasPublicationYear "2023" @default.
• W4362594103 type Work @default.
• W4362594103 citedByCount "0" @default.
• W4362594103 crossrefType "journal-article" @default.
• W4362594103 hasAuthorship W4362594103A5003178040 @default.
• W4362594103 hasAuthorship W4362594103A5023748431 @default.
• W4362594103 hasAuthorship W4362594103A5027234036 @default.
• W4362594103 hasAuthorship W4362594103A5043867874 @default.
• W4362594103 hasAuthorship W4362594103A5045699506 @default.
• W4362594103 hasAuthorship W4362594103A5053069471 @default.
• W4362594103 hasAuthorship W4362594103A5054932703 @default.
• W4362594103 hasAuthorship W4362594103A5056560382 @default.
• W4362594103 hasAuthorship W4362594103A5060097531 @default.
• W4362594103 hasAuthorship W4362594103A5066584293 @default.
• W4362594103 hasAuthorship W4362594103A5072528156 @default.
• W4362594103 hasAuthorship W4362594103A5081196478 @default.
• W4362594103 hasAuthorship W4362594103A5090010000 @default.
• W4362594103 hasConcept C121608353 @default.
• W4362594103 hasConcept C126322002 @default.
• W4362594103 hasConcept C172313692 @default.
• W4362594103 hasConcept C185592680 @default.
• W4362594103 hasConcept C2777176818 @default.
• W4362594103 hasConcept C2777944059 @default.
• W4362594103 hasConcept C2780482068 @default.
• W4362594103 hasConcept C502942594 @default.
• W4362594103 hasConcept C530470458 @default.
• W4362594103 hasConcept C71924100 @default.
• W4362594103 hasConcept C84606932 @default.
• W4362594103 hasConcept C86803240 @default.
• W4362594103 hasConceptScore W4362594103C121608353 @default.
• W4362594103 hasConceptScore W4362594103C126322002 @default.
• W4362594103 hasConceptScore W4362594103C172313692 @default.
• W4362594103 hasConceptScore W4362594103C185592680 @default.
• W4362594103 hasConceptScore W4362594103C2777176818 @default.
• W4362594103 hasConceptScore W4362594103C2777944059 @default.
• W4362594103 hasConceptScore W4362594103C2780482068 @default.
• W4362594103 hasConceptScore W4362594103C502942594 @default.
• W4362594103 hasConceptScore W4362594103C530470458 @default.
• W4362594103 hasConceptScore W4362594103C71924100 @default.
• W4362594103 hasConceptScore W4362594103C84606932 @default.
• W4362594103 hasConceptScore W4362594103C86803240 @default.
• W4362594103 hasIssue "7_Supplement" @default.
• W4362594103 hasLocation W43625941031 @default.
• W4362594103 hasOpenAccess W4362594103 @default.
• W4362594103 hasPrimaryLocation W43625941031 @default.
• W4362594103 hasRelatedWork W2060345758 @default.
• W4362594103 hasRelatedWork W2323968754 @default.
• W4362594103 hasRelatedWork W2477397472 @default.
• W4362594103 hasRelatedWork W2530784802 @default.
• W4362594103 hasRelatedWork W2886595387 @default.
• W4362594103 hasRelatedWork W2913370005 @default.
• W4362594103 hasRelatedWork W2921920460 @default.
• W4362594103 hasRelatedWork W3106991775 @default.
• W4362594103 hasRelatedWork W3200278202 @default.
• W4362594103 hasRelatedWork W4362594103 @default.
• W4362594103 hasVolume "83" @default.
• W4362594103 isParatext "false" @default.
• W4362594103 isRetracted "false" @default.
• W4362594103 workType "article" @default.