2026-04-17T03:44:38Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/114932025-10-24T10:35:18Zcom_2072_378070com_2072_378040col_2072_378092

00925njm 22002777a 4500 dc Mondaza Hernandez, Jose Lucinio author Sanchez-Bustos, Paloma author López Álvarez, María author Romagosa Pérez-Portabell, Cleofé author Valverde Morales, Claudia Maria author Moura, David author Peña-Chilet, Maria author Cordero Varela, Juan Antonio author 2024-05-23T10:09:19Z 2024-05-23T10:09:19Z 2024-05-17 Leiomyosarcoma; Soft-tissue sarcoma; Trabectedin Leiomiosarcoma; Sarcoma de teixit tou; Trabectedina Leiomiosarcoma; Sarcoma de tejido blando; Trabectedina HMGA1 is a structural epigenetic chromatin factor that has been associated with tumor progression and drug resistance. Here, we reported the prognostic/predictive value of HMGA1 for trabectedin in advanced soft-tissue sarcoma (STS) and the effect of inhibiting HMGA1 or the mTOR downstream pathway in trabectedin activity. The prognostic/predictive value of HMGA1 expression was assessed in a cohort of 301 STS patients at mRNA (n = 133) and protein level (n = 272), by HTG EdgeSeq transcriptomics and immunohistochemistry, respectively. The effect of HMGA1 silencing on trabectedin activity and gene expression profiling was measured in leiomyosarcoma cells. The effect of combining mTOR inhibitors with trabectedin was assessed on cell viability in vitro studies, whereas in vivo studies tested the activity of this combination. HMGA1 mRNA and protein expression were significantly associated with worse progression-free survival of trabectedin and worse overall survival in STS. HMGA1 silencing sensitized leiomyosarcoma cells for trabectedin treatment, reducing the spheroid area and increasing cell death. The downregulation of HGMA1 significantly decreased the enrichment of some specific gene sets, including the PI3K/AKT/mTOR pathway. The inhibition of mTOR, sensitized leiomyosarcoma cultures for trabectedin treatment, increasing cell death. In in vivo studies, the combination of rapamycin with trabectedin downregulated HMGA1 expression and stabilized tumor growth of 3-methylcholantrene-induced sarcoma-like models. HMGA1 is an adverse prognostic factor for trabectedin treatment in advanced STS. HMGA1 silencing increases trabectedin efficacy, in part by modulating the mTOR signaling pathway. Trabectedin plus mTOR inhibitors are active in preclinical models of sarcoma, downregulating HMGA1 expression levels and stabilizing tumor growth. This study was partially funded by the Spanish group for research on sarcoma (GEIS; Grant number: GEIS-38) and by PharmaMar (institutional research grant; Grant number: NA). http://hdl.handle.net/11351/11493 Tumors de parts toves - Tractament Medicaments antineoplàstics - Ús terapèutic Resistència als medicaments DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Connective and Soft Tissue::Neoplasms, Muscle Tissue::Leiomyosarcoma Other subheadings::Other subheadings::Other subheadings::/drug therapy PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents Other subheadings::Other subheadings::/therapeutic use ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de tejido conjuntivo y de tejidos blandos::neoplasias de tejido muscular::leiomiosarcoma Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos Otros calificadores::Otros calificadores::/uso terapéutico HMGA1 regulates trabectedin sensitivity in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study