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

Selected publications

Díez-Villanueva A, Sanz-Pamplona R, Carreras-Torres R, Moratalla-Navarro F, Alonso MH, Paré-Brunet L, Aussó S, Guinó E, Solé X, Cordero D, Salazar R, Berdasco M, Peinado MA, Moreno V

DNA methylation events in transcription factors and gene expression changes in colon cancer

Epigenomics, 2020 Sep 22 , .
Aim: Gain insight about the role of DNA methylation in the malignant growth of colon cancer. Patients & methods: Methylation and gene expression from 90 adjacent-tumor paired tissues and 48 healthy tissues were analyzed. Tumor genes whose change in expression was explained by changes in methylation were identified using linear models adjusted for tumor stromal content. Results: No differences in methylation were found between adjacent and healthy tissues, but clear differences were found between adjacent and tumor samples. We identified hypermethylated CpG islands located in promoter regions that drive differential gene expression of transcription factors and their target genes. Conclusion: Changes in methylation of a few genes provoke important changes in gene expression, by expanding the signal through transcription activation/repression.
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Moron-Lopez S, Urrea V, Dalmau J, Lopez M, Puertas MC, Ouchi D, Gómez A, Passaes C, Mothe B, Brander C, Saez-Cirion A, Clotet B, Esteller M, Berdasco M, Martinez-Picado J

The genome-wide methylation profile of CD4+ T cells from HIV-infected individuals identifies distinct patterns associated with disease progression

Clinical Infectious Diseases, 2020, Jul 26:ciaa1047 , .
Background: Human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in progression of HIV infection. However, it is also known that viral infections can modify cellular DNA methylation patterns. Therefore, changes in the methylation of CpG islands might modulate progression of HIV infection. Methods: 85 samples were analyzed: 21 elite controllers (EC), 21 HIV-infected subjects before combination antiretroviral therapy (cART) (viremic, 93,325 HIV-1 RNA copies/ml) and under suppressive cART (cART, median of 17 months, <50 HIV-1 RNA copies/ml), and 22 HIV-negative donors (HIVneg). We analyzed the methylation pattern of 485,577 CpG in DNA from peripheral CD4+ T lymphocytes. We selected the most differentially methylated gene (TNF) and analyzed its specific methylation, mRNA expression, and plasma protein levels in 5 individuals before and after initiation of cART. Results: We observed 129 methylated CpG sites (associated with 43 gene promoters) for which statistically significant differences were recorded in viremic vs HIVneg, 162 CpG sites (55 gene promoters) in viremic vs cART, 441 CpG sites (163 gene promoters) in viremic vs EC, but none in EC vs HIVneg. The TNF promoter region was hypermethylated in viremic vs HIVneg, cART, and EC. Moreover, we observed greater plasma levels of TNF in viremic individuals than in EC, cART, and HIVneg. Conclusions: Our study shows that genome methylation patterns vary depending on HIV infection status and progression profile and that these variations might have an impact on controlling HIV infection in the absence of cART.
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Oriol-Tordera B, Berdasco M, Llano A, Mothe B, Gálvez C, Martinez-Picado J, Carrillo J, Blanco J, Duran-Castells C, Ganoza C, Sanchez J, Clotet B, Calle ML, Sánchez-Pla A, Esteller M, Brander C, Ruiz-Riol M

Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control

PLOS Pathogens 2020, 16(8):e1008678. , .
GWAS, immune analyses and biomarker screenings have identified host factors associated with in vivo HIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g. PARP9, MX1, and USP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g. CXCR5 and TCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cART treated and elite controllers HIV-1 infected individuals (n = 37). These data provide the first evidence that host genes critically involved in immune control of the virus are under methylation regulation in HIV-1 infection. These insights may offer new opportunities to identify novel mechanisms of in vivo virus control and may prove crucial for the development of future therapeutic interventions aimed at HIV-1 cure.
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Cossío FP, Esteller M, Berdasco M

Towards a more precise therapy in cancer: Exploring epigenetic complexity.

Curr Opin Chem Biol 29 May 2020, 57 41-49. Epub 29 May 2020
A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours.
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Ganesan A, Arimondo PB, Rots MG, Jeronimo C, Berdasco M

The timeline of epigenetic drug discovery: from reality to dreams

Clinical Epigenetics 2019, 11(1):174. , .
he flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. All three families of epigenetic proteins-readers, writers, and erasers-are druggable targets that can be addressed through small-molecule inhibitors. At present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. Here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. Finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. To turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design.
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Berdasco M, Esteller M

Clinical Epigenetics: seizing opportunities for translation

Nature Reviews Genetics, 2019. 20(2):109-127. , .
Biomarker discovery and validation are necessary for improving the prediction of clinical outcomes and patient monitoring. Despite considerable interest in biomarker discovery and development, improvements in the range and quality of biomarkers are still needed. The main challenge is how to integrate preclinical data to obtain a reliable biomarker that can be measured with acceptable costs in routine clinical practice. Epigenetic alterations are already being incorporated as valuable candidates in the biomarker field. Furthermore, their reversible nature offers a promising opportunity to ameliorate disease symptoms by using epigenetic-based therapy. Thus, beyond helping to understand disease biology, clinical epigenetics is being incorporated into patient management in oncology, as well as being explored for clinical applicability for other human pathologies such as neurological and infectious diseases and immune system disorders.
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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