TY - JOUR T1 - Drug-target identification in COVID-19 disease mechanisms using computational systems biology approaches. JF - Front Immunol Y1 - 2024 A1 - Niarakis, Anna A1 - Ostaszewski, Marek A1 - Mazein, Alexander A1 - Kuperstein, Inna A1 - Kutmon, Martina A1 - Gillespie, Marc E A1 - Funahashi, Akira A1 - Acencio, Marcio Luis A1 - Hemedan, Ahmed A1 - Aichem, Michael A1 - Klein, Karsten A1 - Czauderna, Tobias A1 - Burtscher, Felicia A1 - Yamada, Takahiro G A1 - Hiki, Yusuke A1 - Hiroi, Noriko F A1 - Hu, Finterly A1 - Pham, Nhung A1 - Ehrhart, Friederike A1 - Willighagen, Egon L A1 - Valdeolivas, Alberto A1 - Dugourd, Aurélien A1 - Messina, Francesco A1 - Esteban-Medina, Marina A1 - Peña-Chilet, Maria A1 - Rian, Kinza A1 - Soliman, Sylvain A1 - Aghamiri, Sara Sadat A1 - Puniya, Bhanwar Lal A1 - Naldi, Aurélien A1 - Helikar, Tomáš A1 - Singh, Vidisha A1 - Fernández, Marco Fariñas A1 - Bermudez, Viviam A1 - Tsirvouli, Eirini A1 - Montagud, Arnau A1 - Noël, Vincent A1 - Ponce-de-Leon, Miguel A1 - Maier, Dieter A1 - Bauch, Angela A1 - Gyori, Benjamin M A1 - Bachman, John A A1 - Luna, Augustin A1 - Piñero, Janet A1 - Furlong, Laura I A1 - Balaur, Irina A1 - Rougny, Adrien A1 - Jarosz, Yohan A1 - Overall, Rupert W A1 - Phair, Robert A1 - Perfetto, Livia A1 - Matthews, Lisa A1 - Rex, Devasahayam Arokia Balaya A1 - Orlic-Milacic, Marija A1 - Gomez, Luis Cristobal Monraz A1 - De Meulder, Bertrand A1 - Ravel, Jean Marie A1 - Jassal, Bijay A1 - Satagopam, Venkata A1 - Wu, Guanming A1 - Golebiewski, Martin A1 - Gawron, Piotr A1 - Calzone, Laurence A1 - Beckmann, Jacques S A1 - Evelo, Chris T A1 - D'Eustachio, Peter A1 - Schreiber, Falk A1 - Saez-Rodriguez, Julio A1 - Dopazo, Joaquin A1 - Kuiper, Martin A1 - Valencia, Alfonso A1 - Wolkenhauer, Olaf A1 - Kitano, Hiroaki A1 - Barillot, Emmanuel A1 - Auffray, Charles A1 - Balling, Rudi A1 - Schneider, Reinhard KW - Computer Simulation KW - COVID-19 KW - drug repositioning KW - Humans KW - SARS-CoV-2 KW - Systems biology AB -

INTRODUCTION: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing.

METHODS: Extensive community work allowed an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework can link biomolecules from omics data analysis and computational modelling to dysregulated pathways in a cell-, tissue- or patient-specific manner. Drug repurposing using text mining and AI-assisted analysis identified potential drugs, chemicals and microRNAs that could target the identified key factors.

RESULTS: Results revealed drugs already tested for anti-COVID-19 efficacy, providing a mechanistic context for their mode of action, and drugs already in clinical trials for treating other diseases, never tested against COVID-19.

DISCUSSION: The key advance is that the proposed framework is versatile and expandable, offering a significant upgrade in the arsenal for virus-host interactions and other complex pathologies.

VL - 14 ER - TY - JOUR T1 - The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery. JF - J Transl Med Y1 - 2024 A1 - Esteban-Medina, Marina A1 - Loucera, Carlos A1 - Rian, Kinza A1 - Velasco, Sheyla A1 - Olivares-González, Lorena A1 - Rodrigo, Regina A1 - Dopazo, Joaquin A1 - Peña-Chilet, Maria KW - Animals KW - Mice KW - Retinitis pigmentosa KW - Signal Transduction AB -

BACKGROUND: Retinitis pigmentosa is the prevailing genetic cause of blindness in developed nations with no effective treatments. In the pursuit of unraveling the intricate dynamics underlying this complex disease, mechanistic models emerge as a tool of proven efficiency rooted in systems biology, to elucidate the interplay between RP genes and their mechanisms. The integration of mechanistic models and drug-target interactions under the umbrella of machine learning methodologies provides a multifaceted approach that can boost the discovery of novel therapeutic targets, facilitating further drug repurposing in RP.

METHODS: By mapping Retinitis Pigmentosa-related genes (obtained from Orphanet, OMIM and HPO databases) onto KEGG signaling pathways, a collection of signaling functional circuits encompassing Retinitis Pigmentosa molecular mechanisms was defined. Next, a mechanistic model of the so-defined disease map, where the effects of interventions can be simulated, was built. Then, an explainable multi-output random forest regressor was trained using normal tissue transcriptomic data to learn causal connections between targets of approved drugs from DrugBank and the functional circuits of the mechanistic disease map. Selected target genes involvement were validated on rd10 mice, a murine model of Retinitis Pigmentosa.

RESULTS: A mechanistic functional map of Retinitis Pigmentosa was constructed resulting in 226 functional circuits belonging to 40 KEGG signaling pathways. The method predicted 109 targets of approved drugs in use with a potential effect over circuits corresponding to nine hallmarks identified. Five of those targets were selected and experimentally validated in rd10 mice: Gabre, Gabra1 (GABARα1 protein), Slc12a5 (KCC2 protein), Grin1 (NR1 protein) and Glr2a. As a result, we provide a resource to evaluate the potential impact of drug target genes in Retinitis Pigmentosa.

CONCLUSIONS: The possibility of building actionable disease models in combination with machine learning algorithms to learn causal drug-disease interactions opens new avenues for boosting drug discovery. Such mechanistically-based hypotheses can guide and accelerate the experimental validations prioritizing drug target candidates. In this work, a mechanistic model describing the functional disease map of Retinitis Pigmentosa was developed, identifying five promising therapeutic candidates targeted by approved drug. Further experimental validation will demonstrate the efficiency of this approach for a systematic application to other rare diseases.

VL - 22 IS - 1 ER - TY - JOUR T1 - A Comprehensive Analysis of 21 Actionable Pharmacogenes in the Spanish Population: From Genetic Characterisation to Clinical Impact. JF - Pharmaceutics Y1 - 2023 A1 - Núñez-Torres, Rocío A1 - Pita, Guillermo A1 - Peña-Chilet, Maria A1 - López-López, Daniel A1 - Zamora, Jorge A1 - Roldán, Gema A1 - Herráez, Belén A1 - Alvarez, Nuria A1 - Alonso, María Rosario A1 - Dopazo, Joaquin A1 - González-Neira, Anna AB -

The implementation of pharmacogenetics (PGx) is a main milestones of precision medicine nowadays in order to achieve safer and more effective therapies. Nevertheless, the implementation of PGx diagnostics is extremely slow and unequal worldwide, in part due to a lack of ethnic PGx information. We analysed genetic data from 3006 Spanish individuals obtained by different high-throughput (HT) techniques. Allele frequencies were determined in our population for the main 21 actionable PGx genes associated with therapeutical changes. We found that 98% of the Spanish population harbours at least one allele associated with a therapeutical change and, thus, there would be a need for a therapeutical change in a mean of 3.31 of the 64 associated drugs. We also identified 326 putative deleterious variants that were not previously related with PGx in 18 out of the 21 main PGx genes evaluated and a total of 7122 putative deleterious variants for the 1045 PGx genes described. Additionally, we performed a comparison of the main HT diagnostic techniques, revealing that after whole genome sequencing, genotyping with the PGx HT array is the most suitable solution for PGx diagnostics. Finally, all this information was integrated in the Collaborative Spanish Variant Server to be available to and updated by the scientific community.

VL - 15 IS - 4 ER - TY - JOUR T1 - Crosstalk between Metabolite Production and Signaling Activity in Breast Cancer. JF - Int J Mol Sci Y1 - 2023 A1 - Cubuk, Cankut A1 - Loucera, Carlos A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin AB -

The reprogramming of metabolism is a recognized cancer hallmark. It is well known that different signaling pathways regulate and orchestrate this reprogramming that contributes to cancer initiation and development. However, recent evidence is accumulating, suggesting that several metabolites could play a relevant role in regulating signaling pathways. To assess the potential role of metabolites in the regulation of signaling pathways, both metabolic and signaling pathway activities of Breast invasive Carcinoma (BRCA) have been modeled using mechanistic models. Gaussian Processes, powerful machine learning methods, were used in combination with SHapley Additive exPlanations (SHAP), a recent methodology that conveys causality, to obtain potential causal relationships between the production of metabolites and the regulation of signaling pathways. A total of 317 metabolites were found to have a strong impact on signaling circuits. The results presented here point to the existence of a complex crosstalk between signaling and metabolic pathways more complex than previously was thought.

VL - 24 IS - 8 ER - TY - JOUR T1 - A crowdsourcing database for the copy-number variation of the Spanish population. JF - Hum Genomics Y1 - 2023 A1 - López-López, Daniel A1 - Roldán, Gema A1 - Fernandez-Rueda, Jose L A1 - Bostelmann, Gerrit A1 - Carmona, Rosario A1 - Aquino, Virginia A1 - Perez-Florido, Javier A1 - Ortuno, Francisco A1 - Pita, Guillermo A1 - Núñez-Torres, Rocío A1 - González-Neira, Anna A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin AB -

BACKGROUND: Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants.

RESULTS: Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/ .

CONCLUSION: SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.

VL - 17 IS - 1 ER - TY - JOUR T1 - microRNAs-mediated regulation of insulin signaling in white adipose tissue during aging: Role of caloric restriction. JF - Aging Cell Y1 - 2023 A1 - Corrales, Patricia A1 - Martin-Taboada, Marina A1 - Vivas-García, Yurena A1 - Torres, Lucia A1 - Ramirez-Jimenez, Laura A1 - Lopez, Yamila A1 - Horrillo, Daniel A1 - Vila-Bedmar, Rocio A1 - Barber-Cano, Eloisa A1 - Izquierdo-Lahuerta, Adriana A1 - Peña-Chilet, Maria A1 - Martínez, Carmen A1 - Dopazo, Joaquin A1 - Ros, Manuel A1 - Medina-Gomez, Gema AB -

Caloric restriction is a non-pharmacological intervention known to ameliorate the metabolic defects associated with aging, including insulin resistance. The levels of miRNA expression may represent a predictive tool for aging-related alterations. In order to investigate the role of miRNAs underlying insulin resistance in adipose tissue during the early stages of aging, 3- and 12-month-old male animals fed ad libitum, and 12-month-old male animals fed with a 20% caloric restricted diet were used. In this work we demonstrate that specific miRNAs may contribute to the impaired insulin-stimulated glucose metabolism specifically in the subcutaneous white adipose tissue, through the regulation of target genes implicated in the insulin signaling cascade. Moreover, the expression of these miRNAs is modified by caloric restriction in middle-aged animals, in accordance with the improvement of the metabolic state. Overall, our work demonstrates that alterations in posttranscriptional gene expression because of miRNAs dysregulation might represent an endogenous mechanism by which insulin response in the subcutaneous fat depot is already affected at middle age. Importantly, caloric restriction could prevent this modulation, demonstrating that certain miRNAs could constitute potential biomarkers of age-related metabolic alterations.

ER - TY - JOUR T1 - Real-world evidence with a retrospective cohort of 15,968 COVID-19 hospitalized patients suggests 21 new effective treatments. JF - Virol J Y1 - 2023 A1 - Loucera, Carlos A1 - Carmona, Rosario A1 - Esteban-Medina, Marina A1 - Bostelmann, Gerrit A1 - Muñoyerro-Muñiz, Dolores A1 - Villegas, Román A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin AB -

PURPOSE: Despite the extensive vaccination campaigns in many countries, COVID-19 is still a major worldwide health problem because of its associated morbidity and mortality. Therefore, finding efficient treatments as fast as possible is a pressing need. Drug repurposing constitutes a convenient alternative when the need for new drugs in an unexpected medical scenario is urgent, as is the case with COVID-19.

METHODS: Using data from a central registry of electronic health records (the Andalusian Population Health Database), the effect of prior consumption of drugs for other indications previous to the hospitalization with respect to patient outcomes, including survival and lymphocyte progression, was studied on a retrospective cohort of 15,968 individuals, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020.

RESULTS: Covariate-adjusted hazard ratios and analysis of lymphocyte progression curves support a significant association between consumption of 21 different drugs and better patient survival. Contrarily, one drug, furosemide, displayed a significant increase in patient mortality.

CONCLUSIONS: In this study we have taken advantage of the availability of a regional clinical database to study the effect of drugs, which patients were taking for other indications, on their survival. The large size of the database allowed us to control covariates effectively.

VL - 20 IS - 1 ER - TY - JOUR T1 - Visualization of automatically combined disease maps and pathway diagrams for rare diseases. JF - Front Bioinform Y1 - 2023 A1 - Gawron, Piotr A1 - Hoksza, David A1 - Piñero, Janet A1 - Peña-Chilet, Maria A1 - Esteban-Medina, Marina A1 - Fernandez-Rueda, Jose Luis A1 - Colonna, Vincenza A1 - Smula, Ewa A1 - Heirendt, Laurent A1 - Ancien, François A1 - Grouès, Valentin A1 - Satagopam, Venkata P A1 - Schneider, Reinhard A1 - Dopazo, Joaquin A1 - Furlong, Laura I A1 - Ostaszewski, Marek AB -

Investigation of molecular mechanisms of human disorders, especially rare diseases, require exploration of various knowledge repositories for building precise hypotheses and complex data interpretation. Recently, increasingly more resources offer diagrammatic representation of such mechanisms, including disease-dedicated schematics in pathway databases and disease maps. However, collection of knowledge across them is challenging, especially for research projects with limited manpower. In this article we present an automated workflow for construction of maps of molecular mechanisms for rare diseases. The workflow requires a standardized definition of a disease using Orphanet or HPO identifiers to collect relevant genes and variants, and to assemble a functional, visual repository of related mechanisms, including data overlays. The diagrams composing the final map are unified to a common systems biology format from CellDesigner SBML, GPML and SBML+layout+render. The constructed resource contains disease-relevant genes and variants as data overlays for immediate visual exploration, including embedded genetic variant browser and protein structure viewer. We demonstrate the functionality of our workflow on two examples of rare diseases: Kawasaki disease and retinitis pigmentosa. Two maps are constructed based on their corresponding identifiers. Moreover, for the retinitis pigmentosa use-case, we include a list of differentially expressed genes to demonstrate how to tailor the workflow using omics datasets. In summary, our work allows for an ad-hoc construction of molecular diagrams combined from different sources, preserving their layout and graphical style, but integrating them into a single resource. This allows to reduce time consuming tasks of prototyping of a molecular disease map, enabling visual exploration, hypothesis building, data visualization and further refinement. The code of the workflow is open and accessible at https://gitlab.lcsb.uni.lu/minerva/automap/.

VL - 3 ER - TY - JOUR T1 - Discovering potential interactions between rare diseases and COVID-19 by combining mechanistic models of viral infection with statistical modeling. JF - Hum Mol Genet Y1 - 2022 A1 - López-Sánchez, Macarena A1 - Loucera, Carlos A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin AB -

Recent studies have demonstrated a relevant role of the host genetics in the COVID-19 prognosis. Most of the 7000 rare diseases described to date have a genetic component, typically highly penetrant. However, this vast spectrum of genetic variability remains yet unexplored with respect to possible interactions with COVID-19. Here, a mathematical mechanistic model of the COVID-19 molecular disease mechanism has been used to detect potential interactions between rare disease genes and the COVID-19 infection process and downstream consequences. Out of the 2518 disease genes analyzed, causative of 3854 rare diseases, a total of 254 genes have a direct effect on the COVID-19 molecular disease mechanism and 207 have an indirect effect revealed by a significant strong correlation. This remarkable potential of interaction occurs for more than 300 rare diseases. Mechanistic modeling of COVID-19 disease map has allowed a holistic systematic analysis of the potential interactions between the loss of function in known rare disease genes and the pathological consequences of COVID-19 infection. The results identify links between disease genes and COVID-19 hallmarks and demonstrate the usefulness of the proposed approach for future preventive measures in some rare diseases.

ER - TY - JOUR T1 - An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in Mice. JF - Antioxidants (Basel) Y1 - 2022 A1 - Olivares-González, Lorena A1 - Velasco, Sheyla A1 - Gallego, Idoia A1 - Esteban-Medina, Marina A1 - Puras, Gustavo A1 - Loucera, Carlos A1 - Martínez-Romero, Alicia A1 - Peña-Chilet, Maria A1 - Pedraz, José Luis A1 - Rodrigo, Regina AB -

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in mice, a model of RP, as well as on LPS-stimulated BV2 cells. The EFA supplement was orally administered to mice from postnatal day (P)9 to P18. At P18, the electrical activity of the retina was examined by electroretinography (ERG) and innate behavior in response to light were measured. Retinal degeneration was studied via histology including the TUNEL assay and microglia immunolabeling. Microglia polarization (M1/M2) was assessed by flow cytometry, qPCR, ELISA and histology. Redox status was analyzed by measuring antioxidant enzymes and markers of oxidative damage. Interestingly, the EFA supplement ameliorated retinal dysfunction and degeneration by improving ERG recording and sensitivity to light, and reducing photoreceptor cell loss. The EFA supplement reduced inflammation and microglia activation attenuating M1 markers as well as inducing a shift to the M2 phenotype in mouse retinas and LPS-stimulated BV2 cells. It also reduced oxidative stress markers of lipid peroxidation and carbonylation. These findings could open up new therapeutic opportunities based on resolving inflammation with oral supplementation with SPMs such as the EFA supplement.

VL - 12 IS - 1 ER - TY - JOUR T1 - Towards a metagenomics machine learning interpretable model for understanding the transition from adenoma to colorectal cancer. JF - Sci Rep Y1 - 2022 A1 - Casimiro-Soriguer, Carlos S A1 - Loucera, Carlos A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin AB -

Gut microbiome is gaining interest because of its links with several diseases, including colorectal cancer (CRC), as well as the possibility of being used to obtain non-intrusive predictive disease biomarkers. Here we performed a meta-analysis of 1042 fecal metagenomic samples from seven publicly available studies. We used an interpretable machine learning approach based on functional profiles, instead of the conventional taxonomic profiles, to produce a highly accurate predictor of CRC with better precision than those of previous proposals. Moreover, this approach is also able to discriminate samples with adenoma, which makes this approach very promising for CRC prevention by detecting early stages in which intervention is easier and more effective. In addition, interpretable machine learning methods allow extracting features relevant for the classification, which reveals basic molecular mechanisms accounting for the changes undergone by the microbiome functional landscape in the transition from healthy gut to adenoma and CRC conditions. Functional profiles have demonstrated superior accuracy in predicting CRC and adenoma conditions than taxonomic profiles and additionally, in a context of explainable machine learning, provide useful hints on the molecular mechanisms operating in the microbiota behind these conditions.

VL - 12 IS - 1 ER - TY - JOUR T1 - A comprehensive database for integrated analysis of omics data in autoimmune diseases. JF - BMC Bioinformatics Y1 - 2021 A1 - Martorell-Marugán, Jordi A1 - López-Domínguez, Raúl A1 - García-Moreno, Adrián A1 - Toro-Domínguez, Daniel A1 - Villatoro-García, Juan Antonio A1 - Barturen, Guillermo A1 - Martín-Gómez, Adoración A1 - Troule, Kevin A1 - Gómez-López, Gonzalo A1 - Al-Shahrour, Fátima A1 - González-Rumayor, Víctor A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin A1 - Saez-Rodriguez, Julio A1 - Alarcón-Riquelme, Marta E A1 - Carmona-Sáez, Pedro KW - Autoimmune Diseases KW - Computational Biology KW - Databases, Factual KW - Humans AB -

BACKGROUND: Autoimmune diseases are heterogeneous pathologies with difficult diagnosis and few therapeutic options. In the last decade, several omics studies have provided significant insights into the molecular mechanisms of these diseases. Nevertheless, data from different cohorts and pathologies are stored independently in public repositories and a unified resource is imperative to assist researchers in this field.

RESULTS: Here, we present Autoimmune Diseases Explorer ( https://adex.genyo.es ), a database that integrates 82 curated transcriptomics and methylation studies covering 5609 samples for some of the most common autoimmune diseases. The database provides, in an easy-to-use environment, advanced data analysis and statistical methods for exploring omics datasets, including meta-analysis, differential expression or pathway analysis.

CONCLUSIONS: This is the first omics database focused on autoimmune diseases. This resource incorporates homogeneously processed data to facilitate integrative analyses among studies.

VL - 22 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/34167460?dopt=Abstract ER - TY - JOUR T1 - COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms. JF - Mol Syst Biol Y1 - 2021 A1 - Ostaszewski, Marek A1 - Niarakis, Anna A1 - Mazein, Alexander A1 - Kuperstein, Inna A1 - Phair, Robert A1 - Orta-Resendiz, Aurelio A1 - Singh, Vidisha A1 - Aghamiri, Sara Sadat A1 - Acencio, Marcio Luis A1 - Glaab, Enrico A1 - Ruepp, Andreas A1 - Fobo, Gisela A1 - Montrone, Corinna A1 - Brauner, Barbara A1 - Frishman, Goar A1 - Monraz Gómez, Luis Cristóbal A1 - Somers, Julia A1 - Hoch, Matti A1 - Kumar Gupta, Shailendra A1 - Scheel, Julia A1 - Borlinghaus, Hanna A1 - Czauderna, Tobias A1 - Schreiber, Falk A1 - Montagud, Arnau A1 - Ponce de Leon, Miguel A1 - Funahashi, Akira A1 - Hiki, Yusuke A1 - Hiroi, Noriko A1 - Yamada, Takahiro G A1 - Dräger, Andreas A1 - Renz, Alina A1 - Naveez, Muhammad A1 - Bocskei, Zsolt A1 - Messina, Francesco A1 - Börnigen, Daniela A1 - Fergusson, Liam A1 - Conti, Marta A1 - Rameil, Marius A1 - Nakonecnij, Vanessa A1 - Vanhoefer, Jakob A1 - Schmiester, Leonard A1 - Wang, Muying A1 - Ackerman, Emily E A1 - Shoemaker, Jason E A1 - Zucker, Jeremy A1 - Oxford, Kristie A1 - Teuton, Jeremy A1 - Kocakaya, Ebru A1 - Summak, Gökçe Yağmur A1 - Hanspers, Kristina A1 - Kutmon, Martina A1 - Coort, Susan A1 - Eijssen, Lars A1 - Ehrhart, Friederike A1 - Rex, Devasahayam Arokia Balaya A1 - Slenter, Denise A1 - Martens, Marvin A1 - Pham, Nhung A1 - Haw, Robin A1 - Jassal, Bijay A1 - Matthews, Lisa A1 - Orlic-Milacic, Marija A1 - Senff Ribeiro, Andrea A1 - Rothfels, Karen A1 - Shamovsky, Veronica A1 - Stephan, Ralf A1 - Sevilla, Cristoffer A1 - Varusai, Thawfeek A1 - Ravel, Jean-Marie A1 - Fraser, Rupsha A1 - Ortseifen, Vera A1 - Marchesi, Silvia A1 - Gawron, Piotr A1 - Smula, Ewa A1 - Heirendt, Laurent A1 - Satagopam, Venkata A1 - Wu, Guanming A1 - Riutta, Anders A1 - Golebiewski, Martin A1 - Owen, Stuart A1 - Goble, Carole A1 - Hu, Xiaoming A1 - Overall, Rupert W A1 - Maier, Dieter A1 - Bauch, Angela A1 - Gyori, Benjamin M A1 - Bachman, John A A1 - Vega, Carlos A1 - Grouès, Valentin A1 - Vazquez, Miguel A1 - Porras, Pablo A1 - Licata, Luana A1 - Iannuccelli, Marta A1 - Sacco, Francesca A1 - Nesterova, Anastasia A1 - Yuryev, Anton A1 - de Waard, Anita A1 - Turei, Denes A1 - Luna, Augustin A1 - Babur, Ozgun A1 - Soliman, Sylvain A1 - Valdeolivas, Alberto A1 - Esteban-Medina, Marina A1 - Peña-Chilet, Maria A1 - Rian, Kinza A1 - Helikar, Tomáš A1 - Puniya, Bhanwar Lal A1 - Modos, Dezso A1 - Treveil, Agatha A1 - Olbei, Marton A1 - De Meulder, Bertrand A1 - Ballereau, Stephane A1 - Dugourd, Aurélien A1 - Naldi, Aurélien A1 - Noël, Vincent A1 - Calzone, Laurence A1 - Sander, Chris A1 - Demir, Emek A1 - Korcsmaros, Tamas A1 - Freeman, Tom C A1 - Augé, Franck A1 - Beckmann, Jacques S A1 - Hasenauer, Jan A1 - Wolkenhauer, Olaf A1 - Wilighagen, Egon L A1 - Pico, Alexander R A1 - Evelo, Chris T A1 - Gillespie, Marc E A1 - Stein, Lincoln D A1 - Hermjakob, Henning A1 - D'Eustachio, Peter A1 - Saez-Rodriguez, Julio A1 - Dopazo, Joaquin A1 - Valencia, Alfonso A1 - Kitano, Hiroaki A1 - Barillot, Emmanuel A1 - Auffray, Charles A1 - Balling, Rudi A1 - Schneider, Reinhard KW - Antiviral Agents KW - Computational Biology KW - Computer Graphics KW - COVID-19 KW - Cytokines KW - Data Mining KW - Databases, Factual KW - Gene Expression Regulation KW - Host Microbial Interactions KW - Humans KW - Immunity, Cellular KW - Immunity, Humoral KW - Immunity, Innate KW - Lymphocytes KW - Metabolic Networks and Pathways KW - Myeloid Cells KW - Protein Interaction Mapping KW - SARS-CoV-2 KW - Signal Transduction KW - Software KW - Transcription Factors KW - Viral Proteins AB -

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

VL - 17 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/34664389?dopt=Abstract ER - TY - JOUR T1 - CSVS, a crowdsourcing database of the Spanish population genetic variability. JF - Nucleic Acids Res Y1 - 2021 A1 - Peña-Chilet, Maria A1 - Roldán, Gema A1 - Perez-Florido, Javier A1 - Ortuno, Francisco M A1 - Carmona, Rosario A1 - Aquino, Virginia A1 - López-López, Daniel A1 - Loucera, Carlos A1 - Fernandez-Rueda, Jose L A1 - Gallego, Asunción A1 - Garcia-Garcia, Francisco A1 - González-Neira, Anna A1 - Pita, Guillermo A1 - Núñez-Torres, Rocío A1 - Santoyo-López, Javier A1 - Ayuso, Carmen A1 - Minguez, Pablo A1 - Avila-Fernandez, Almudena A1 - Corton, Marta A1 - Moreno-Pelayo, Miguel Ángel A1 - Morin, Matías A1 - Gallego-Martinez, Alvaro A1 - Lopez-Escamez, Jose A A1 - Borrego, Salud A1 - Antiňolo, Guillermo A1 - Amigo, Jorge A1 - Salgado-Garrido, Josefa A1 - Pasalodos-Sanchez, Sara A1 - Morte, Beatriz A1 - Carracedo, Ángel A1 - Alonso, Ángel A1 - Dopazo, Joaquin KW - Alleles KW - Chromosome Mapping KW - Crowdsourcing KW - Databases, Genetic KW - Exome KW - Gene Frequency KW - Genetic Variation KW - Genetics, Population KW - Genome, Human KW - Genomics KW - Humans KW - Internet KW - Precision Medicine KW - Software KW - Spain AB -

The knowledge of the genetic variability of the local population is of utmost importance in personalized medicine and has been revealed as a critical factor for the discovery of new disease variants. Here, we present the Collaborative Spanish Variability Server (CSVS), which currently contains more than 2000 genomes and exomes of unrelated Spanish individuals. This database has been generated in a collaborative crowdsourcing effort collecting sequencing data produced by local genomic projects and for other purposes. Sequences have been grouped by ICD10 upper categories. A web interface allows querying the database removing one or more ICD10 categories. In this way, aggregated counts of allele frequencies of the pseudo-control Spanish population can be obtained for diseases belonging to the category removed. Interestingly, in addition to pseudo-control studies, some population studies can be made, as, for example, prevalence of pharmacogenomic variants, etc. In addition, this genomic data has been used to define the first Spanish Genome Reference Panel (SGRP1.0) for imputation. This is the first local repository of variability entirely produced by a crowdsourcing effort and constitutes an example for future initiatives to characterize local variability worldwide. CSVS is also part of the GA4GH Beacon network. CSVS can be accessed at: http://csvs.babelomics.org/.

VL - 49 IS - D1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32990755?dopt=Abstract ER - TY - JOUR T1 - A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin. JF - Mol Oncol Y1 - 2021 A1 - Moura, David S A1 - Peña-Chilet, Maria A1 - Cordero Varela, Juan Antonio A1 - Alvarez-Alegret, Ramiro A1 - Agra-Pujol, Carolina A1 - Izquierdo, Francisco A1 - Ramos, Rafael A1 - Ortega-Medina, Luis A1 - Martin-Davila, Francisco A1 - Castilla-Ramirez, Carolina A1 - Hernandez-Leon, Carmen Nieves A1 - Romagosa, Cleofe A1 - Vaz Salgado, Maria Angeles A1 - Lavernia, Javier A1 - Bagué, Silvia A1 - Mayodormo-Aranda, Empar A1 - Vicioso, Luis A1 - Hernández Barceló, Jose Emilio A1 - Rubio-Casadevall, Jordi A1 - de Juan, Ana A1 - Fiaño-Valverde, Maria Concepcion A1 - Hindi, Nadia A1 - Lopez-Alvarez, Maria A1 - Lacerenza, Serena A1 - Dopazo, Joaquin A1 - Gutierrez, Antonio A1 - Alvarez, Rosa A1 - Valverde, Claudia A1 - Martinez-Trufero, Javier A1 - Martin-Broto, Javier AB -

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.

VL - 15 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/33983674?dopt=Abstract ER - TY - JOUR T1 - Genome-scale mechanistic modeling of signaling pathways made easy: A bioconductor/cytoscape/web server framework for the analysis of omic data JF - Computational and Structural Biotechnology Journal Y1 - 2021 A1 - Rian, Kinza A1 - Hidalgo, Marta R. A1 - Cubuk, Cankut A1 - Falco, Matias M. A1 - Loucera, Carlos A1 - Esteban-Medina, Marina A1 - Alamo-Alvarez, Inmaculada A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin VL - 19 UR - https://linkinghub.elsevier.com/retrieve/pii/S2001037021002038 JO - Computational and Structural Biotechnology Journal ER - TY - JOUR T1 - Immunotherapy in nonsmall-cell lung cancer: current status and future prospects for liquid biopsy. JF - Cancer Immunol Immunother Y1 - 2021 A1 - Brozos-Vázquez, Elena María A1 - Díaz-Peña, Roberto A1 - García-González, Jorge A1 - León-Mateos, Luis A1 - Mondelo-Macía, Patricia A1 - Peña-Chilet, Maria A1 - López-López, Rafael KW - Animals KW - Biomarkers, Tumor KW - Carcinoma, Non-Small-Cell Lung KW - Cell-Free Nucleic Acids KW - Exosomes KW - Humans KW - Immunotherapy KW - Liquid Biopsy KW - Lung Neoplasms AB -

Immunotherapy has been one of the great advances in the recent years for the treatment of advanced tumors, with nonsmall-cell lung cancer (NSCLC) being one of the cancers that has benefited most from this approach. Currently, the only validated companion diagnostic test for first-line immunotherapy in metastatic NSCLC patients is testing for programmed death ligand 1 (PD-L1) expression in tumor tissues. However, not all patients experience an effective response with the established selection criteria and immune checkpoint inhibitors (ICIs). Liquid biopsy offers a noninvasive opportunity to monitor disease in patients with cancer and identify those who would benefit the most from immunotherapy. This review focuses on the use of liquid biopsy in immunotherapy treatment of NSCLC patients. Circulating tumor cells (CTCs), cell-free DNA (cfDNA) and exosomes are promising tools for developing new biomarkers. We discuss the current application and future implementation of these parameters to improve therapeutic decision-making and identify the patients who will benefit most from immunotherapy.

VL - 70 IS - 5 ER - TY - JOUR T1 - Mechanistic modeling of the SARS-CoV-2 disease map. JF - BioData Min Y1 - 2021 A1 - Rian, Kinza A1 - Esteban-Medina, Marina A1 - Hidalgo, Marta R A1 - Cubuk, Cankut A1 - Falco, Matias M A1 - Loucera, Carlos A1 - Gunyel, Devrim A1 - Ostaszewski, Marek A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin AB -

Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map. In this framework, the detailed activity of the human signaling circuits related to the viral infection, covering from the entry and replication mechanisms to the downstream consequences as inflammation and antigenic response, can be inferred from gene expression experiments. Moreover, the effect of potential interventions, such as knock-downs, or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied. This freely available tool not only provides an unprecedentedly detailed view of the mechanisms of viral invasion and the consequences in the cell but has also the potential of becoming an invaluable asset in the search for efficient antiviral treatments.

VL - 14 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/33478554?dopt=Abstract ER - TY - JOUR T1 - Mutational Characterization of Cutaneous Melanoma Supports Divergent Pathways Model for Melanoma Development. JF - Cancers (Basel) Y1 - 2021 A1 - Millán-Esteban, David A1 - Peña-Chilet, Maria A1 - García-Casado, Zaida A1 - Manrique-Silva, Esperanza A1 - Requena, Celia A1 - Bañuls, José A1 - Lopez-Guerrero, Jose Antonio A1 - Rodríguez-Hernández, Aranzazu A1 - Traves, Víctor A1 - Dopazo, Joaquin A1 - Virós, Amaya A1 - Kumar, Rajiv A1 - Nagore, Eduardo AB -

According to the divergent pathway model, cutaneous melanoma comprises a nevogenic group with a propensity to melanocyte proliferation and another one associated with cumulative solar damage (CSD). While characterized clinically and epidemiologically, the differences in the molecular profiles between the groups have remained primarily uninvestigated. This study has used a custom gene panel and bioinformatics tools to investigate the potential molecular differences in a thoroughly characterized cohort of 119 melanoma patients belonging to nevogenic and CSD groups. We found that the nevogenic melanomas had a restricted set of mutations, with the prominently mutated gene being . The CSD melanomas, in contrast, showed mutations in a diverse group of genes that included , , , and . We thus provide evidence that nevogenic and CSD melanomas constitute different biological entities and highlight the need to explore new targeted therapies.

VL - 13 IS - 20 ER - TY - JOUR T1 - Real world evidence of calcifediol or vitamin D prescription and mortality rate of COVID-19 in a retrospective cohort of hospitalized Andalusian patients. JF - Sci Rep Y1 - 2021 A1 - Loucera, Carlos A1 - Peña-Chilet, Maria A1 - Esteban-Medina, Marina A1 - Muñoyerro-Muñiz, Dolores A1 - Villegas, Román A1 - López-Miranda, José A1 - Rodríguez-Baño, Jesús A1 - Túnez, Isaac A1 - Bouillon, Roger A1 - Dopazo, Joaquin A1 - Quesada Gomez, Jose Manuel KW - Calcifediol KW - COVID-19 KW - Female KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Retrospective Studies KW - Spain KW - Survival Analysis KW - Vitamin D AB -

COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61-0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization.

VL - 11 IS - 1 ER - TY - JOUR T1 - A versatile workflow to integrate RNA-seq genomic and transcriptomic data into mechanistic models of signaling pathways. JF - PLoS Comput Biol Y1 - 2021 A1 - Garrido-Rodriguez, Martín A1 - López-López, Daniel A1 - Ortuno, Francisco M A1 - Peña-Chilet, Maria A1 - Muñoz, Eduardo A1 - Calzado, Marco A A1 - Dopazo, Joaquin KW - Algorithms KW - Cell Line, Tumor KW - Computational Biology KW - Databases, Factual KW - Gene Expression Profiling KW - Genomics KW - High-Throughput Nucleotide Sequencing KW - Humans KW - Models, Theoretical KW - mutation KW - RNA-seq KW - Signal Transduction KW - Software KW - Transcriptome KW - whole exome sequencing KW - Workflow AB -

MIGNON is a workflow for the analysis of RNA-Seq experiments, which not only efficiently manages the estimation of gene expression levels from raw sequencing reads, but also calls genomic variants present in the transcripts analyzed. Moreover, this is the first workflow that provides a framework for the integration of transcriptomic and genomic data based on a mechanistic model of signaling pathway activities that allows a detailed biological interpretation of the results, including a comprehensive functional profiling of cell activity. MIGNON covers the whole process, from reads to signaling circuit activity estimations, using state-of-the-art tools, it is easy to use and it is deployable in different computational environments, allowing an optimized use of the resources available.

VL - 17 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/33571195?dopt=Abstract ER - TY - JOUR T1 - Drug repurposing for COVID-19 using machine learning and mechanistic models of signal transduction circuits related to SARS-CoV-2 infection. JF - Signal Transduct Target Ther Y1 - 2020 A1 - Loucera, Carlos A1 - Esteban-Medina, Marina A1 - Rian, Kinza A1 - Falco, Matias M A1 - Dopazo, Joaquin A1 - Peña-Chilet, Maria KW - Computational Chemistry KW - COVID-19 KW - drug repositioning KW - Humans KW - Machine Learning KW - Molecular Docking Simulation KW - Molecular Targeted Therapy KW - Proteins KW - SARS-CoV-2 KW - Signal Transduction VL - 5 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/33311438?dopt=Abstract ER - TY - JOUR T1 - Immune Cell Associations with Cancer Risk. JF - iScience Y1 - 2020 A1 - Palomero, Luis A1 - Galván-Femenía, Ivan A1 - de Cid, Rafael A1 - Espín, Roderic A1 - Barnes, Daniel R A1 - Blommaert, Eline A1 - Gil-Gil, Miguel A1 - Falo, Catalina A1 - Stradella, Agostina A1 - Ouchi, Dan A1 - Roso-Llorach, Albert A1 - Violan, Concepció A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin A1 - Extremera, Ana Isabel A1 - García-Valero, Mar A1 - Herranz, Carmen A1 - Mateo, Francesca A1 - Mereu, Elisabetta A1 - Beesley, Jonathan A1 - Chenevix-Trench, Georgia A1 - Roux, Cecilia A1 - Mak, Tak A1 - Brunet, Joan A1 - Hakem, Razq A1 - Gorrini, Chiara A1 - Antoniou, Antonis C A1 - Lázaro, Conxi A1 - Pujana, Miquel Angel AB -

Proper immune system function hinders cancer development, but little is known about whether genetic variants linked to cancer risk alter immune cells. Here, we report 57 cancer risk loci associated with differences in immune and/or stromal cell contents in the corresponding tissue. Predicted target genes show expression and regulatory associations with immune features. Polygenic risk scores also reveal associations with immune and/or stromal cell contents, and breast cancer scores show consistent results in normal and tumor tissue. SH2B3 links peripheral alterations of several immune cell types to the risk of this malignancy. Pleiotropic SH2B3 variants are associated with breast cancer risk in BRCA1/2 mutation carriers. A retrospective case-cohort study indicates a positive association between blood counts of basophils, leukocytes, and monocytes and age at breast cancer diagnosis. These findings broaden our knowledge of the role of the immune system in cancer and highlight promising prevention strategies for individuals at high risk.

VL - 23 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32622267?dopt=Abstract ER - TY - JOUR T1 - Mechanistic models of signaling pathways deconvolute the glioblastoma single-cell functional landscapeAbstract JF - NAR Cancer Y1 - 2020 A1 - Falco, Matias M A1 - Peña-Chilet, Maria A1 - Loucera, Carlos A1 - Hidalgo, Marta R A1 - Dopazo, Joaquin VL - 2 UR - https://academic.oup.com/narcancer/article/doi/10.1093/narcan/zcaa011/5862620http://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdfhttp://academic.oup.com/narcancer/article-pdf/2/2/zcaa011/33428092/zcaa011.pdf IS - 2 ER - TY - JOUR T1 - Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments. JF - Cells Y1 - 2020 A1 - Cubuk, Cankut A1 - Can, Fatma E A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin KW - Female KW - Gene Expression Regulation, Neoplastic KW - Humans KW - Male KW - Neoplasms KW - Signal Transduction AB -

Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression.

VL - 9 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32610626?dopt=Abstract ER - TY - JOUR T1 - Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial. JF - J Immunother Cancer Y1 - 2020 A1 - Martin-Broto, Javier A1 - Hindi, Nadia A1 - Grignani, Giovanni A1 - Martinez-Trufero, Javier A1 - Redondo, Andres A1 - Valverde, Claudia A1 - Stacchiotti, Silvia A1 - Lopez-Pousa, Antonio A1 - D'Ambrosio, Lorenzo A1 - Gutierrez, Antonio A1 - Perez-Vega, Herminia A1 - Encinas-Tobajas, Victor A1 - de Alava, Enrique A1 - Collini, Paola A1 - Peña-Chilet, Maria A1 - Dopazo, Joaquin A1 - Carrasco-Garcia, Irene A1 - Lopez-Alvarez, Maria A1 - Moura, David S A1 - Lopez-Martin, Jose A KW - Adult KW - Aged KW - Antineoplastic Agents, Immunological KW - Female KW - Humans KW - Male KW - Middle Aged KW - Nivolumab KW - Sarcoma KW - Sunitinib KW - Young Adult AB -

BACKGROUND: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).

METHODS: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).

RESULTS: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).

CONCLUSIONS: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.

VL - 8 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/33203665?dopt=Abstract ER - TY - JOUR T1 - Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial. JF - Lancet Oncol Y1 - 2020 A1 - Martin-Broto, Javier A1 - Cruz, Josefina A1 - Penel, Nicolas A1 - Le Cesne, Axel A1 - Hindi, Nadia A1 - Luna, Pablo A1 - Moura, David S A1 - Bernabeu, Daniel A1 - de Alava, Enrique A1 - Lopez-Guerrero, Jose Antonio A1 - Dopazo, Joaquin A1 - Peña-Chilet, Maria A1 - Gutierrez, Antonio A1 - Collini, Paola A1 - Karanian, Marie A1 - Redondo, Andres A1 - Lopez-Pousa, Antonio A1 - Grignani, Giovanni A1 - Diaz-Martin, Juan A1 - Marcilla, David A1 - Fernandez-Serra, Antonio A1 - Gonzalez-Aguilera, Cristina A1 - Casali, Paolo G A1 - Blay, Jean-Yves A1 - Stacchiotti, Silvia KW - Aged KW - Female KW - Follow-Up Studies KW - Humans KW - Indazoles KW - Male KW - Middle Aged KW - Neoplasm Metastasis KW - Prognosis KW - Prospective Studies KW - Protein Kinase Inhibitors KW - Pyrimidines KW - Response Evaluation Criteria in Solid Tumors KW - Solitary Fibrous Tumors KW - Sulfonamides KW - Survival Rate AB -

BACKGROUND: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.

FINDINGS: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).

INTERPRETATION: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

VL - 21 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/32066540?dopt=Abstract ER - TY - JOUR T1 - Exploring the druggable space around the Fanconi anemia pathway using machine learning and mechanistic models. JF - BMC Bioinformatics Y1 - 2019 A1 - Esteban-Medina, Marina A1 - Peña-Chilet, Maria A1 - Loucera, Carlos A1 - Dopazo, Joaquin KW - Databases, Factual KW - Fanconi Anemia KW - Genomics KW - Humans KW - Machine Learning KW - Phenotype KW - Proteins KW - Signal Transduction AB -

BACKGROUND: In spite of the abundance of genomic data, predictive models that describe phenotypes as a function of gene expression or mutations are difficult to obtain because they are affected by the curse of dimensionality, given the disbalance between samples and candidate genes. And this is especially dramatic in scenarios in which the availability of samples is difficult, such as the case of rare diseases.

RESULTS: The application of multi-output regression machine learning methodologies to predict the potential effect of external proteins over the signaling circuits that trigger Fanconi anemia related cell functionalities, inferred with a mechanistic model, allowed us to detect over 20 potential therapeutic targets.

CONCLUSIONS: The use of artificial intelligence methods for the prediction of potentially causal relationships between proteins of interest and cell activities related with disease-related phenotypes opens promising avenues for the systematic search of new targets in rare diseases.

VL - 20 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/31266445?dopt=Abstract ER - TY - JOUR T1 - Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial. JF - Lancet Oncol Y1 - 2019 A1 - Martin-Broto, Javier A1 - Stacchiotti, Silvia A1 - Lopez-Pousa, Antonio A1 - Redondo, Andres A1 - Bernabeu, Daniel A1 - de Alava, Enrique A1 - Casali, Paolo G A1 - Italiano, Antoine A1 - Gutierrez, Antonio A1 - Moura, David S A1 - Peña-Chilet, Maria A1 - Diaz-Martin, Juan A1 - Biscuola, Michele A1 - Taron, Miguel A1 - Collini, Paola A1 - Ranchere-Vince, Dominique A1 - Garcia Del Muro, Xavier A1 - Grignani, Giovanni A1 - Dumont, Sarah A1 - Martinez-Trufero, Javier A1 - Palmerini, Emanuela A1 - Hindi, Nadia A1 - Sebio, Ana A1 - Dopazo, Joaquin A1 - Dei Tos, Angelo Paolo A1 - LeCesne, Axel A1 - Blay, Jean-Yves A1 - Cruz, Josefina KW - Adult KW - Aged KW - Angiogenesis Inhibitors KW - Antineoplastic Agents KW - Female KW - Humans KW - Indazoles KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Pyrimidines KW - Response Evaluation Criteria in Solid Tumors KW - Soft Tissue Neoplasms KW - Solitary Fibrous Tumors KW - Sulfonamides KW - Survival Analysis AB -

BACKGROUND: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.

METHODS: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.

FINDINGS: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).

INTERPRETATION: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.

FUNDING: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.

VL - 20 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/30578023?dopt=Abstract ER - TY - JOUR T1 - Using mechanistic models for the clinical interpretation of complex genomic variation JF - Scientific Reports Y1 - 2019 A1 - Peña-Chilet, Maria A1 - Esteban-Medina, Marina A1 - Falco, Matias M. A1 - Rian, Kinza A1 - Hidalgo, Marta R. A1 - Loucera, Carlos A1 - Dopazo, Joaquin VL - 9 UR - http://www.nature.com/articles/s41598-019-55454-7http://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7.pdfhttp://www.nature.com/articles/s41598-019-55454-7 IS - 1 JO - Sci Rep ER -