Scientific publications
Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression
Segovia C (1,2,3), San José-Enériz E (2,4), Munera-Maravilla E (1,3), Martínez-Fernández M (1,2,3,5), Garate L (2,6), Miranda E (2,4), Vilas-Zornoza A (2,4), Lodewijk I (1), Rubio C (2,3), Segrelles C (1,2), Valcárcel LV (2,4,7), Rabal O (8), Casares N (9), Bernardini A (1,2), Suarez-Cabrera C (3), López-Calderón FF 1,2,3, Fortes P (10), Casado JA (11), Dueñas M (1,2,3), Villacampa F (2,3), Lasarte JJ (9), Guerrero-Ramos F (3,12), de Velasco G (3,13), Oyarzabal J (8), Castellano D (1,2,13), Agirre X (14,15), Prósper F (16,17,18), Paramio JM (19,20,21).
(1) Molecular Oncology Unit CIEMAT, Madrid, Spain.
(2) Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.
(3) Institute of Biomedical Research, University Hospital '12 de Octubre', Madrid, Spain.
(4) Hemato-oncology Program, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Pamplona, Spain.
(5) Mobile Genomes and Disease Laboratory CIMUS, Universidad de Santiago de Compostela, La Coruña, Spain.
(6) Hematology and Cell Therapy Department, Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain.
(7) TECNUN, University of Navarra, San Sebastián, Spain.
(8) Small Molecule Discovery Platform, Molecular Therapeutics Program, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.
(9) Immunology and Immunotherapy Program, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Pamplona, Spain.
(10) Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Pamplona, Spain.
(11) Division of Hematopoietic Innovative Therapies (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras and Advanced Therapies Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.
(12) Urology Department, University Hospital '12 de Octubre', Madrid, Spain.
(13) Medical Oncology Department, University Hospital '12 de Octubre', Madrid, Spain.
(14) Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.
(15) Hemato-oncology Program, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Pamplona, Spain.
(16) Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.
(17) Hemato-oncology Program, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Pamplona, Spain.
(18) Hematology and Cell Therapy Department, Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain.
(19) Molecular Oncology Unit CIEMAT, Madrid, Spain.
(20) Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.
(21) Institute of Biomedical Research, University Hospital '12 de Octubre', Madrid, Spain.
ABSTRACT
Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances1,2. Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer3,4.
The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients5-8. 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 (PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; 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.
CITATION Nat Med. 2019 Jul 3. doi: 10.1038/s41591-019-0499-y
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