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Segovia, Cristina; San José-Enériz, Edurne; Munera-Maravilla, Ester; Martínez-Fernández, Mónica; Garate, Leire; Miranda, Estíbaliz; Vilas-Zornoza, Amaia; Lodewijk, Iris; Rubio, Carolina; Segrelles, Carmen; Valcárcel, Luis Vitores; Rabal, Obdulia; Casares, Noelia; Bernardini, Alejandra; Suarez-Cabrera, Cristian; López-Calderón, Fernando F; Fortes, Puri; Casado, José A; Dueñas, Marta; Villacampa, Felipe; Lasarte, Juan José; Guerrero-Ramos, Félix; de Velasco, Guillermo; Oyarzabal, Julen; Castellano, Daniel; Agirre, Xabier; Prósper, Felipe; Paramio, Jesús M
Nature medicine, 07/2019, Letnik: 25, Številka: 7Journal Article
Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances . Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer . The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients . Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten ; Trp53 ; Rb1 ; Rbl1 ) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.
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Dostop do baze podatkov JCR je dovoljen samo uporabnikom iz Slovenije. Vaš trenutni IP-naslov ni na seznamu dovoljenih za dostop, zato je potrebna avtentikacija z ustreznim računom AAI.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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