dianas 7(1) > Segovia etal

dianas | Vol 7 Num 1 | marzo 2018 | e201803a23

Inhibition of a G9a-Ezh2 network triggers an immune-mediated bladder cancer regression.

Cristina Segovia^a, Edurne San José-Enériz, Monica Martínez-Fernández, Ester Munera-Maravilla, Leire Garate, Estíbaliz Miranda, Iris Lodewijk, Carolina Rubio, Carmen Segrelles, Obdulia Rabal, Noelia Casares, Alejandra Bernardini, José A Casado, Marta Dueñas, Felipe Villacampa, Juan José Lasarte, Felix Guerrero, Guillermo de Velasco, Julen Oyarzabal, Daniel Castellano, Xabier Aguirre, Felipe Prósper, Jesús M. Paramio

CIEMAT.

a. crismaitia@gmail.com

III Congreso de Señalización Celular, SECUAH 2018.
20-22 de marzo, 2018. Universidad de Alcalá. Alcalá de Henares, Madrid. España.
Sesión A2 – Cáncer

Abstract

Bladder cancer (BC) represents the 7th most common cancer in men and the 17th in women. At diagnoses, approximately 75% of patients present with a non-muscle invasive disease (NMIBC) and the remaining 25% of the patients showed muscle-invasive cancer (MIBC). This pathology classification determines the treatment. NMIBC are treated by transurethral resection, which can be followed by intravesical instillation with BCG or mytomycin. However, a large proportion of NMIBC show a high rate of recurrence and, in some cases, these recurrences display increased aggressiveness progressing to MIBC. The current therapeutic options of MIBC include radical cystectomy, and cisplatin-based chemotherapy with poor clinical results. In a high proportion of the cases, the disease progress showing metastatic spreading, accounting for an extremely low survival. Moreover, an important fraction of the MIBC patients presents severe comorbidities due to other pathological conditions being considered ineligible for chemotherapy with few or no therapeutic alternatives. Recently, immune checkpoint inhibitors, based on PD-1 or PDL1 blockade, have demonstrated promising results in advanced BC patients. However, the number of patients that may benefit from these therapies is still limited, as a relevant fraction does not show objective responses accounting for only partial overall survival increase. Consequently, there is a need of new avenues in advanced BC management. The molecular landscape of BC has identified multiple alterations in genes governing chromatin organization and histone modifications. The epigenomic profiles correlate with the clinical outcome indicating possible therapeutic options for patients. Regarding the chromatin-remodeler genes, the involvement of EZH2 has gained relevance in the last years, due to its implication in multiple malignancies, especially in BC. EZH2 is a histone methyltransferase that regulates gene silencing through H3K27me3 marks. G9a is another histone-methyltransferase generating H3K9me2. In addition G9a can also monomethylate H3K27 thus priming for EZH2 activity. Moreover G9a and EZH2 interact in vivo and in vitro to modulate specific gene silencing through specific genomic recruitment to a subset of target genes. However the possible roles of G9A in BC have not been elucidated. Here we report that increased expression of G9a is characteristic of BC cases in association with poor clinical outcome of bladder cancer patient. This opens the possibility that G9a inhibitors can be of benefit in the management of BC. We show that a recently described G9a/DNMT dual inhibitor (CM272) is active in BC cells in vitro and in vivo. Moreover, we also demonstrate a synergistic effect of this inhibitor with cisplatin, the current chemotherapeutic for advanced bladder cancer, in vitro and in vivo. Remarkably, in a transgenic mouse model of metastatic bladder cancer, based on the simultaneous deletion of various tumor suppressor genes in urothelial cells, the combined treatment resulted in almost complete tumor and metastasis eradication mainly through activation of immune system. These findings, support new and promising opportunities for the therapy of bladder cancer.