Epigenetic Therapies

  • Epigenetic Therapies Group

Summary

In the last years, we are witnessing tremendous progress related to the scientific knowledge on epigenetic contribution and its development toward translational research leading to implementation in the clinic. The Epigenetic Therapies group is focused on elucidating which epigenetic alterations are druggable targets in a tumor, and the means for their therapeutic exploitation in the framework of Precision Medicine. To this end, we will aim at answering three key questions that would turn this hypothesis into a clinical reality: (1) Which epigenetic alterations are “druggable” targets for cancer management; (2) How can we efficiently treat cancers that depend on epigenetic alterations; and (3) Who would benefit of such epigenetic-based therapeutic strategy?

Research

The research at the Epigenetic Therapies group aims to ascertain the therapeutic benefit of targeting epigenetic alterations in cancer together with an epigenetic-based stratification of the patients to predict therapy response.

We develop the research following three specific aims:

  1. Identification of the epigenetic alterations acting as drivers of the tumor progression (“druggable epigenetic alterations”). We aim to explore the epigenetic network consisting of DNA methylation and discover potential epigenetic drivers that might play a causative role in haematological cancers. We apply the new possibilities offered by CRISPR-dCas9 directed genome targeting to set up epigenome editing systems that target DNA methylation and demethylation to differentially methylated regions identified in cancer cells. By combining these methods and in vitro proliferation assays, we identify those methylation changes that directly stimulate the growth of healthy cells or inhibit the growth of cancerous ones.

  2. Validation of epidrugs that can efficiently revert aberrant epigenomes in cancer. We aim to determine whether cancer cells with genetic alterations affecting epigenetic genes are more susceptible to be treated with epigenetic drugs. To reach this goal, we determine the therapeutic effect in vitro of drugs in cell lines with and without genetic defects. We use commercially available epidrugs when possible, but interestingly we test novel small compounds designed under collaboration (e.g. members of the CM1406 COST action). We perform basic functional assays to test their potential inhibitory effect on tumorigenesis (e.g., MTT, colony formation, wound healing, transwell migration assays, flow cytometry, or apoptosis). Results derived from cell lines are validated in mice models (in collaboration). In parallel, we study the genome-wide epigenetic pattern before and after the treatment with epigenetic drugs to identify main targeted pathways (e.g. CpG methylation arrays for DNMT inhibitors or Chip-seq for histone modifiers drugs).

  3. Stratification of patients based on their epigenetic profile to predict response to immunotherapy.  Commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients via epigenetic regulation of innate and adaptive immunity. The research group aims to identify epigenetic biomarkers of clinical response to immunotherapy in haematological cancer based on the presence and abundance of strain level bacteria. We study the gut microbiome strain-level population structure to identify bacteria that have a beneficial or detrimental effect on response to treatment (shotgun metagenomics) together with a characterization of the epigenome of the immune blood cell (genome-wide CpG methylation analysis). We are focused on two immunotherapy strategies (anti-PD1/PD-L1 and BiTE) that are approved and included into clinical practice in the Spanish Health system for the treatment of Classical Hodgkin lymphoma (cHL) and B-cell acute lymphoblastic leukemia (B-ALL). We aim to correlate epigenetic signatures of responders and non-responders with bacterial diversity and abundance and to create an algorithm of prediction of response.

Awards

  • Postdoctoral Grant from the Foundation of Spanish Association Against Cancer (AECC) to Maria Berdasco (2005-2008).
  • Best Publication Award “VI Premio Ciencias de la Salud Fundación Caja Rural de Granada, Modalidad investigación” (2010) (Berdasco et al., Proceedings of the National Academy of Sciences USA 2009). 
  • Conference Travel Grant from COST (European Cooperation in Science and Technology) in “Chemistry and Molecular Sciences and Technologies (CMST) Domain to María Berdasco (2013)
  • Fellowship from the Innovative Training Networks Marie Skłodowska-Curie Actions (MSCA-ITN-2014-ETN) of the European Union’s Horizon 2020 Program under Chromatin 3D project (nº SEP-210147404) to David J. Hanly (2015-2018).
  • Mobility Grant “Programa Avanzado en Oncologia” from the Foundation of Spanish Association Against Cancer (AECC) to Maria Berdasco (2016).
  • Mobility Grant the Short-term scientific missions (STSM) from COST (European Cooperation in Science and Technology) to David J. Hanly (2018).

Collaborations

  • Prof. Marianne Rots, University Medical Centre Groningen (UMCG), Groningen, The Netherlands.
  • Prof. Paola Arimondo, CNRS Institute Pasteur, Paris, France.
  • Prof. Eran Segal, Weizmann Institute-WIS, Tel Aviv, Israel.
  • Prof. A. Ganesan, University of East Anglia, Norwich, United Kingdom.
  • Prof. Manfred Jung, Freiburg Institute for Advanced Studies, Freiburg, Germany.
  • Dr. Josep María Cruzado, Hospital Universitario de Bellvitge (HUB-IDIBELL), Barcelona, Spain. 
  • Dra. Nuria Sala, Instituto Catalán de Oncología (ICO-L’Hospitalet), Barcelona, Spain. 

People

Current projects

Parietal cells of the Bowman capsule (PECs), regeneration and damage in renal transplantation. Identification of therapeutic targets and cellular therapy with PECs in ischemia-reperfusion.

Project leader:María Berdasco
Code:FIS PI15/00638
Funding:
Start date:01/01/2016
End date:01/01/2019

SRAA blockade in kidney transplant patients with presence of PECs in urine: a randomized clinical trial of valsartan versus placebo

Project leader:María Berdasco
Code:FIS PI18/00910
Funding:
Start date:01/01/2019
End date:31/12/2021