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[Off-Program] G9a/EZH2 Inhibition Contributes to Immune Checkpoint Inhibitor Efficacy in Metastatic Bladder Cancer

Jesús M. Paramio 

1. Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain

2. Biomedical Research Institute of the University Hospital 12 de Octubre, Madrid, Spain

3. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) 

 

 

Bladder cancer (BC) is a current clinical and social problem. At the metastatic stage BC is considered an incurable disease with no therapeutic improvements during the last decades. Recently, immunotherapy has become a new procedure in management of BC patients, however, only and small percentage of patients showed benefit and there is no reliable biomarkers that can predict this response. Through the genomic characterization of BC samples, besides the identification of various molecular subtypes, it became apparent that one of the most prominent features of BC consists in the alteration of chromatin remodeling machinery, thus providing a potential new way of tumor management.

 

We have analyzed the possibility of using G9a as a potential target. G9a catalyzes the H3K9me2 and H3K27me1 thus allowing transcriptional repression by itself and serving as a priming event in the EZH2 catalytic activity to generate H3K27me3 marks. We observed that G9a showed increased expression in BC samples in association with poor clinical outcome. The use of a novel G9a inhibitor revealed its suitability and synergistic effect with Cisplatin in several BC cell lines and allowed the identification of potential mechanisms of resistance. The effectiveness of this inhibitor was further corroborated in a transgenic immunocompetent mouse model of metastatic BC. Whole transcriptome analyses revealed that the effect of the inhibitor, besides affecting H3K9me2 and H3K27me3 marks included the immunogenic cell death in part mediated by endogenous retroviruses reactivation, which facilitate the recruitment of immune cells in vivo. Remarkably the use of this inhibitor potentiates the therapeutic activity of anti-PD-L1 antibody in vivo promoting a sustained antitumor and antimetastatic activity. 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 and provide new potential biomarkers for the identification of patients who benefit from immunotherapies.

 

 

 

I studied Biology at the Autonomous University of Madrid with a specialization in Biochemistry and Molecular Biology. I did my PhD in 1992 under the Supervision of Dr. J.L. Jorcano on the functional roles of differentiation-associated epidermal keratins at CIEMAT. I did two postdoctoral periods at the University of Dundee, Scotland (working with Dr.. David P Lane and Dr. Birgitte E. Lane) in 1994 and at the Oral and Pharyngeal Cancer Branch of the NIH (with Dr. Silvio J. Gutkind) in 2000. Since 2004, I am Head of the Molecular Oncology Unit at the CIEMAT (Madrid, Spain). Since 2014, I am also head of the Cell and Molecular Oncology and Genitourinary Tumor group at the Biomedical Research Institute of the University Hospital 12 de Octubre (Madrid, Spain), and the Research Joint Unit CIEMAT-I+12, which embraces the people from the two groups and includes 38 multidisciplinary researchers (Pathologists, Urologists, Medical Oncologist, Molecular and Cell Biologists, Geneticists, Bioinformaticians, etc.; including 11 Principal Investigators).

 

I have been Principal Investigators of more than 20 grants and I participated in 12 more from different Agencies of Companies (national and international). I authored 130 international journal articles and 7 book chapters, I edited the book “Intermediate filaments” (Springer), and I authored various scientific dissemination articles. I have presented at national and international meetings on different aspects of Cancer Biology and supervised 18 PhD theses.

 

 

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