Programs
Cancer Computational Biology Group
José A. Seoane
Principal Investigator
Biosketch
Biosketch José A. Seoane
José A. Seoane is a cancer computational biologist with international experience in the UK and the US. His background is computer science (Ingeniero Técnico and Ingeniero en Informática at the University of A Coruña, UDC, Spain), and he was later trained in data science (Master in Statistical Learning and Data mining, UNED and Expert in Applied Statistical Methods, UNED). In 2012 he read his PhD dissertation at the University of A Coruña, supervised by Julian Dorado (UDC) and Fernando Martin, Institute of Health Carlos III (ISCIII), funded by a Xunta de Galicia Isabel Barreto Fellowship. His thesis, focused on different models of biomedical data integration, was supported by an Extraordinary PhD Award, Computer Science and Mathematics section, University of A Coruña.
In 2012 he started his first postdoc at the School of Social and Community Medicine, the University of Bristol, under the supervision of Tom Gaunt (Bristol Genetic Epidemiology Lab) and Colin Campbell (Intelligent Systems Lab), where he studied bioinformatics, genetics and genomics, as well as machine learning. During this time, he first authored two papers in the most important journals in bioinformatics, Bioinformatics and PLoS Computational Biology, and he started working with breast cancer datasets, which piqued his interest in cancer systems biology. He then subsequently moved to Christina Curtis’ lab at University of Southern California, Los Angeles, and later to Stanford University, Stanford (CA, USA), first as postdoc and later as Instructor.
During his time at Stanford University, he worked on cancer systems biology and cancer epigenetics, particularly on how chromatin remodeling units’ somatic alterations affects to cancer progression and drug resistance. Partnering with Gerald Crabtree (Stanford University and Howard Hughes Medical Institute Investigator), he proposed a project to follow up on previous findings reported by the Crabtree lab, showing that alteration in SWI/SNF complex alter TOP2A binding.
They hypothesized that since TOP2A is the major target of anthracyclines, modification of chromatin regulator genes could alter drug resistance in breast cancer. The project was funded by Susan G. Komen Foundation under Curtis and Crabtree’s mentorship, as well as others (DoD, PIs Curtis and Crabtree). These results were reported in Nature Medicine. During this time, he also participated in the international analysis team of some Cancer Genome Atlas projects (Esophageal, Gastrointestinal and ATAC-Seq). At Stanford, he had the opportunity to collaborate with top tier cancer researchers including Dennis Slammon (UCLA) and Mike Press (USC) (pioneers in the discovery of role of Her2 amplification in cancer), Carlos Caldas (Cambridge), Mike Snyder (Head of Genetics Department), Laura Attardi, Monte Winslow, Rob West, Calvin Kuo, Howard Chang, Julien Sage, Mike Bassik and Mike Clarke at Stanford. Results from these collaborations published in Nature (4), Science, Cancer Cell (2), PNAS, Molecular Cell, Cancer Discovery (2), JAMA Oncology, and Nature Genetics (2). In 2021 he was awarded with a Ramon y Cajal Fellowship, which supports his appointment as a Group Leader at the Vall d´Hebron Institute of Oncology (VHIO), as of May 2021.
Summary
Jose A. Seoane joined VHIO this year to set up the newly established Cancer Computational Biology Group. Our team leverages epi(genetic) cancer datasets to unmask the molecular mechanisms implicated in cancer initiation, progression, drug resistance and metastasis towards improved outcomes for patients.
We aim to advance insights into the role of chromatin regulatory elements in treatment response and metastasis, develop novel epigenetic synthetic lethality-based therapeutic options, improve patient stratification guided by multi-omics analysis, and seek out novel epigenetic biomarkers of treatment response.
We have previously shown how the genetic modifiers of chromatin structure are associated with chemotherapy resistance in breast cancer (Seoane et al. 2019)*. Our group aims to establish how these epigenetic alterations affect drug resistance and how epigenetic therapies can be used to target tumor suppressor genes.
We are also exploring how the machine learning-based integration of multi-omic datasets can facilitate the discovery of new cancer subgroups and biomarkers, as well as help to better predict treatment outcomes and drug response.
Our group has participated/participates in multiple international consortia including The Cancer Genome Atlas, the Human Tumor Atlas Network, Cancer Target Discovery and Development (CTD 2) Network, and, most recently, AURORA (metastatic breast cancer multi-omic cohort).
Strategic goals
- Understand the role of chromatin regulatory elements in treatment response and metastasis.
- Discover new epigenetic biomarkers of drug response.
- Potentiate therapeutic options by combining epigenetic therapies with other agents.
Highlights
- VHIO’s Cancer Computational Biology Group was established in May 2021.
- Jose A. Seoane’s Ramon y Cajal Fellowship started this year.
- Jose A. Seoane received a grant from the Ministerio de Ciencia e Innovación to explore epigenetic synthetic lethality mechanisms.
- Our group joined the AURORA metastatic breast cancer consortium.
- José Liñares received his PhD in December 2021.
Horizons
- Determine epigenetic synthetic lethality changes in gastrointestinal cancers.
- Investigate the epigenetic changes in post hormone treatment ER+ and its association with metastatic breast cancer.
- Deconvolute the epithelial and stromal components from ductal carcinoma in situ.
- Identify cell-cycle based signature of treatment prediction in colon cancer.
PI paper pick 2021
- Kamber RA, Nishiga Y, Morton B, Banuelos AM, Barkal AA, Vences-Catalán F, Gu M, Fernandez D, Seoane JA, Yao D, Liu K, Lin S, Spees K, Curtis C, Jerby-Arnon L, Weissman IL, Sage J, Bassik MC. Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis. Nature. 2021 Sep;597(7877):549-554.
- Lo YH, Kolahi KS, Du Y, Chang CY, Krokhotin A, Nair A, Sobba WD, Karlsson K, Jones SJ, Longacre TA, Mah AT, Tercan B, Sockell A, Xu H, Seoane JA, Chen J, Shmulevich I, Weissman JS, Curtis C, Califano A, Fu H, Crabtree GR, Kuo CJ. A CRISPR/Cas9-Engineered ARID1A-Deficient Human Gastric Cancer Organoid Model Reveals Essential and Nonessential Modes of Oncogenic Transformation. Cancer Discov. 2021 Jun;11(6):1562-1581
- Chaikovsky AC, Li C, Jeng EE, Loebell S, Lee MC, Murray CW, Cheng R, Demeter J, Swaney DL, Chen SH, Newton BW, Johnson JR, Drainas AP, Shue YT, Seoane JA, Srinivasan P, He A, Yoshida A, Hipkins SQ, McCrea E, Poltorack CD, Krogan NJ, Diehl JA, Kong C, Jackson PK, Curtis C, Petrov DA, Bassik MC, Winslow MM, Sage J. The AMBRA1 E3 ligase adaptor regulates the stability of cyclin D. Nature. 2021 Apr;592(7856):794-798.
- Flowers BM, Xu H, Mulligan AS, Hanson KJ, Seoane JA, Vogel H, Curtis C, Wood LD, Attardi LD. Cell of Origin Influences Pancreatic Cancer Subtype. Cancer Discov. 2021 Mar;11(3):660-677.
Projects
- Targeting synthetic lethality in Chromatin Regulatory Genes for gastrointestinal cancer treatment (Ref: PID2020-115097RA-I00).
Funding Agency: Agencia Estatal de Investigación.
Duration: 9/2021-8/2025.
PI: Jose A. Seoane - Ramon y Cajal Fellowship:
Funding Agency: Agencia Estatal de Investigación.
Duration: 2021-2025.
Cellular Plasticity & Cancer Group
María Abad
Principal Investigator
Biosketch
Biosketch María Abad
María Abad carried out her predoctoral studies at the Institute for Biomedical Research (IIB, CSIC-UAM, Madrid), during which time she identified the tumor suppressor ING1b as a critical regulator of cellular senescence. She was awarded her PhD in Biochemistry, Molecular Biology and Biomedicine by the Universidad Autónoma de Madrid in 2008.
In 2009, she joined Manuel Serrano’s lab as a Postdoctoral Fellow at the Spanish National Cancer Research Centre (CNIO - Madrid), where her research centered on stem cells and cellular reprogramming. During this period, she demonstrated for the first time that cellular reprograming in living organisms is feasible, and triggers the acquisition of totipotency features. This work, published in Nature, was considered a Notable Advance of the Year 2013 by Nature Medicine, receiving several prizes and coverage in various scientific journals.
After this first report, the group discovered an interesting crosstalk between tumor suppressors, damage-induced cellular senescence, and in vivo reprograming – the findings of which were recently published in Science.
In 2014, María joined a world leader in the field of tissue regeneration, E. Olson, at the UT Southwestern Medical Center (Dallas, USA), where she studied the role of cellular dedifferentiation in heart repair, and revealed the importance of Notch signaling pathway during cardiomyoctes reprogramming.
In October 2016, she set up her own laboratory and VHIO´s Cellular Plasticity & Cancer Group, focusing on the interplay between stem cells, cellular plasticity and cancer.
She has received several prizes and awards, including the prestigious Ramón y Cajal Grant for young investigators and a Fero Foundation Fellowship. Her research has also been awarded with grants from the Spanish Ministry of Economy and Competitiveness (MINECO), “La Caixa” Foundation (Health Research Program), and the Health Research Grant from Mutua Madrileña Foundation, among others.
Summary
We focus on the interplay between stress responses, cellular plasticity and cancer. Cellular plasticity is now recognized as a critical feature of cancer cells, enabling them to transit between different cellular states and promote tumor growth, disease progression after therapy, and metastasis.
Our group has previously reported that inducing dedifferentiation with the so-called Yamanaka factors can lead to the development of a variety of tumors. We have also demonstrated that tissue damage -the main driver of cancer- triggers the onset of cellular senescence which then induces dedifferentiation and the acquisition of stem cell properties in vivo.
These findings have important therapeutic implications given that chemotherapy and radiotherapy – cornerstones for the treatment of most cancers – could have the side effect of inducing stemness in non- stem cancer cells and, in turn, possibly contribute to tumor recurrence and cancer cell spread.
Our main objective is to advance insights into the mechanisms and players implicated in this process, with the ultimate goal of developing novel therapies based on the inhibition of cancer cell plasticity.
Recent results have demonstrated that some genomic regions, previously considered as non-coding (including lncRNAs), contain small open reading frames encoding for evolutionary conserved, unannotated microproteins. The few that have been identified to date assume key functions in elemental cellular processes, leading to a new level of complexity with major implications – from basic research to the clinical setting.
Over the past five years, our efforts have focused on identifying and characterizing novel cancer microproteins which could be novel actors in carcinogenesis. We have discovered five new cancer microproteins and have obtained compelling evidence in vitro and in vivo that four of them act as novel tumor suppressors, inducing cell cycle arrest, differentiation or inhibition of mesenchymal traits in cancer cells. In addition, using a peptidomics approach, we have identified a set of microproteins secreted by pancreatic tumors, either soluble or secreted in exosomes. These novel microproteins could be crucial cellular messengers for pancreatic cancer metastasis.
The identification of tumor-microproteins could be key to advancing insights into cancer physiopathology. Moreover, they could also serve as novel cancer biomarkers for the early detection of disease and patient stratification for tailored therapies, as well as therapeutic targets.
In 2021, we have continued to characterize our identified cancer microproteins and have published our work on pTUNAR, a microprotein that regulates neural differentiation through the modulation of calcium dynamics (Senís et al. 2021). In addition, we have contributed a book chapter on the role of Myc in in vivo reprogramming (Senís et al. 2021). Please see our paper pick for 2021 below.
Finally, we have embarked on a collaborative project to study therapy-induced tumoral senescence and its potential as a therapeutic target and prognostic biomarker, funded by the Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer).
Strategic goals
- Advance insights into the interplay between therapy-induced senescence, cellular plasticity and cancer.
- Decipher the molecular mechanisms governing the acquisition of stem cell properties during tumorigenesis and after therapy.
- Discover and characterize novel microproteins involved in cancer cell plasticity.
- Develop novel anti-cancer therapies based on the inhibition of cancer cell plasticity.
Highlights
- Our PI, María Abad, organized the first symposium on microproteins at the 43rd virtual Annual Meeting of the Spanish Society of Biochemistry & Molecular Biology (SEBBM), 19-22 July, Barcelona, Spain.
- We published our work identifying pTUNAR, a novel microprotein that regulates neural differentiation.
- We published a book chapter describing a versatile toolbox to study the role of Myc in in vivo reprogramming.
- We were awarded with a coordinated grant from the Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer), to study the therapy-induced tumoral senescence and its potential as a therapeutic target and prognostic biomarker.
- Our PhD student, Marion Martínez, was awarded with a ”la Caixa” Foundation Doctoral Fellowship INPhINIT – RETAINING, 2021.
Horizons
- Develop cell-penetrating versions of our microproteins as new therapeutic targets.
- Characterize the newly-identified microproteins in cancer patients-plasma.
- Research the effect of therapy-induced senescence in tumor immunogencity.
- Investigate the tumor-stroma crosstalk after chemo/radiotherapy in PDAC and its impact on tumor cell plasticity.
PI paper pick 2021
- Senís E, Esgleas M, Najas S, Jiménez-Sábado V, Bertani C, Giménez-Alejandre M, Escriche A, Ruiz-Orera J, Hergueta-Redondo M, Jiménez M, Giralt A, Nuciforo P, Albà MM, Peinado H, Del Toro D, Hove-Madsen L, Götz M, Abad M. TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics. Front Cell Dev Biol. 2021 Dec 31;9:747667.
- Senís E, Mosteiro L, Grimm D, Abad M. A Versatile In Vivo System to Study Myc in Cell Reprogramming. Methods Mol Biol. 2021;2318:267-279.
Projects
- Tumoral senescence induced by anti-cancer therapies constitutes a novel prognostic biomarker and a therapeutic target.
Reference: PRYCO211023SERR.
Spanish Association Against Cancer - AECC.
Award Period: 9/2021-8/2026
Co-PI: María Abad. - Defining the Role of Exosome-Secreted Micropeptides in Pancreatic Cancer. number: HR18-00256.
Health Research Grant - ”la Caixa”
Award Period: 9/2019-8/2022.
PI: Maria Abad. - Identificación y Análisis del Microproteoma del Cáncer de Páncreas: Los Micropéptidos como Nuevas Dianas Terapéuticas y Biomarcadores Tumorales Fundación.
XVI Convocatoria de Ayudas a la Investigación en Salud.
Fundación Mutua Madrileña.
Award Period: 01/09/2019-30/08/2022.
PI: Maria Abad. - Mining the Microproteome for New Molecular Targets in Cancer. RTI2018-102046-B-I00.
Spanish Ministry of Economy and Competitiveness.
Award Period: 1/2019-12/2021.
PI: Maria Abad.
AWARDS AND RECOGNITION 2021
- We were awarded with a coordinated grant from the Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer), to study the therapy-induced tumoral senescence and its potential as a therapeutic target and prognostic biomarker.
- Our PhD student, Marion Martínez, was awarded with a ”la Caixa” Foundation Doctoral Fellowship INPhINIT – RETAINING, 2021.
FULL LIST OF PUBLICATIONS 2021
- Senís E, Esgleas M, Najas S, Jiménez-Sábado V, Bertani C, Giménez-Alejandre M, Escriche A, Ruiz-Orera J, Hergueta-Redondo M, Jiménez M, Giralt A, Nuciforo P, Albà MM, Peinado H, Del Toro D, Hove-Madsen L, Götz M, Abad M. TUNAR lncRNA Encodes a Microprotein that Regulates Neural Differentiation and Neurite Formation by Modulating Calcium Dynamics. Front Cell Dev Biol. 2021 Dec 31;9:747667.
- Senís E, Mosteiro L, Grimm D, Abad M. A Versatile In Vivo System to Study Myc in Cell Reprogramming. Methods Mol Biol. 2021;2318:267-279.
Chromatin Dynamics in Cancer Group
Sandra Peiró
Principal Investigator
Biosketch
Biosketch Sandra Peiró
VHIO’s Chromatin Dynamics in Cancer Group is comprised of 2 postdocs (1 MD PhD, 1 PhD), 3 predocs, 1 Masters student, and 1 technician (with a 70% female:30% male ratio).
Our projects focus on chromatin dynamics, epigenetics, epithelial-to-mesenchymal transition (EMT) and cancer, are highly ambitious yet successful to-date thanks to close collaboration and connectivity between myself and my group members.
We provide multidisciplinary training and guidance to our PhD students, exposing them to a wide array of techniques and experimental systems throughout their studies. They also attend international meetings of excellence throughout the course of their training.
Our lab was previously located at the Parc de Recerca Biomèdica de Barcelona (PRBB) – a hub of several independent research centers. The proximity to other cutting-edge research institutes facilitated our interaction and collaboration with different groups – partnerships that we that we continue to uphold. Additionally, we still have access to all PRBB’s core facilities including the Confocal and the Ultrasequencing Units as well as the Animal, Proteomics, and Microarray Facilities.
Since Sandra Peiró’s incorporation at VHIO in 2016, her group has published two research papers and has established major collaborations with medical oncologists from the Vall d’Hebron University Hospital (HUVH). Thus, in addition to basic research, her team has initiated three different pre-clinical/translational studies in collaboration with medical oncologists from our Hospital, with financial support received from the ”la Caixa” Foundation, and the pharmaceutical companies BeiGene, Epigene, and Zenith.
Peiró’s group also has multidisciplinary expertise in molecular biology and genome-wide studies:
- Genomic approaches: RNA-seq, ATAC-seq, ChIP-seq
- Ex vivoand in vivoculture of primary human tumor cells
- Establishment of patient-derived xenografts from cholangiocarcinoma (CCA) and NUT-midline carcinoma (NMC) patients
- CCA cell lines genetically-engineered with CRISPR/Cas9. These cells are currently used in our laboratory for negative and positive genome-wide screening upon drug treatments.
Importantly, we work well as a team thanks to the superb interaction between our members. As Principal Investigator, I encourage everyone — from post-docs to technicians — to voice their opinions and express their ideas, with mutual respect for each other. Members also benefit from trainings of excellence to both foster and nurture their future professional growth.
Summary
Our laboratory seeks to better understand how epigenetics and chromatin structure and dynamics affect cell behavior, with specific focus on cancer. Through our comprehensive studies, we aim to dissect the role of epigenetic changes in cancer, identify mechanisms of response and resistance to anti-cancer medicines, and explore new therapeutic opportunities.
Over the last few years, we have elucidated epigenetic changes during EMT and cancer progression, and discovered a new histone H3 modification (oxidized H3) enriched in heterochromatin that is implicated in chromatin condensation and the transition to a metastatic cell fate(Iturbide el al. 2015, Herranz et al. 2016, Cebrià-Costa et al. 2020)*. We have also discovered an important role for lamin B1 in the reorganization of 3D chromatin structure during EMT (Pascual-Reguant et al. 2018)**.
Dedicated to fully applying these insights to the epigenetic landscape and 3D structure during this malignant transformation, we have adopted chromosome conformation–based techniques together with ChIP-seq, ATAC-seq and RNA-seq. By combining these data with excellent computational and statistical tools in standard cancer models, such as cancer cell lines, and in a large and unique collection of patient-derived xenograft (PDX) models, we will continue to navigate this largely uncharted area which shows great promise in the early diagnosis of disease.
We are equally committed to describing the association of chromatin conformation modifications with the acquisition of malignant traits and evaluating the functional consequences of these developments in genes and pathways. Next steps will focus on deciphering how these alterations occur at the molecular level and more precisely identifying these putative culprits for future targeted therapy.
* Iturbide A, Pascual-Reguant L, Fargas L, Cebrià JP, Alsina B, García de Herreros A, Peiró S. LOXL2 Oxidizes Methylated TAF10 and Controls TFIID-Dependent Genes during Neural Progenitor Differentiation. Mol Cell. 2015 Jun 4;58(5):755-66.
Herranz N, Dave N, Millanes-Romero A, Pascual-Reguant L, Morey L, Díaz VM, Lórenz-Fonfría V, Gutierrez-Gallego R, Jerónimo C, Iturbide A, Di Croce L, García de Herreros A, Peiró S. Lysyl oxidase-like 2 (LOXL2) oxidizes trimethylated lysine 4 in histone H3. FEBS J. 2016 Dec;283(23):4263-4273.
Cebrià-Costa JP, Pascual-Reguant L, Gonzalez-Perez A, Serra-Bardenys G, Querol J, Cosín M, Verde G, Cigliano RA, Sanseverino W, Segura-Bayona S, Iturbide A, Andreu D, Nuciforo P, Bernado-Morales C, Rodilla V, Arribas J, Yelamos J, de Herreros AG, Stracker TH, Peiró S. LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells. Oncogene. 2020 Jan;39(1):79-121.
** Pascual-Reguant L, Blanco E, Galan S, Le Dily F, Cuartero Y, Serra-Bardenys G, Di Carlo V, Iturbide A, Cebrià-Costa JP, Nonell L, de Herreros AG, Di Croce L, Marti-Renom MA, Peiró S. Lamin B1 mapping reveals the existence of dynamic and functional eurchromatin lamin B1 domains. Nat Commun. 2018 Aug 24;9(1):3420.
Strategic goals
The two main goals of our laboratory are as follows:
- Understand the 3D structure of chromatin and its dynamics in cancer from a basic research perspective.
- Identify epigenetics features associated with diagnosis, treatment and drug resistance in ER+ breast cancer, gastrointestinal and hepatobiliary malignancies, and NUT-midline carcinomas.
Specifically:
- Which molecular events direct chromatin movements?
- Are these events due to the specific binding of a subset of transcription factors?
- - What are the drivers associated with chromatin architecture reversible changes?
- During the process of metastasis cells go through an intermediate state. Does this state possess a specific and genomic architecture that determines metastatic fate? Could we use the underlying molecular mechanisms to inhibit metastasis?
- What is the role of oxidized H3 in solid tumors? Could we inhibit this oxidation using a peptide-based therapy?
- Are epigenetic dysregulations associated with gastrointestinal and hepatobiliary malignancies? Can Epidrug be applied to treat these malignancies?
- Which are the epigenetic biomarkers that will enable us to stratify gastrointestinal and hepatobiliary cancer patients for more effective treatments?
Highlights
- We have consolidated our collaboration with VHIO’s Gastrointestinal & Endocrine Tumors Group through a grant received from the La Marató TV3 Foundation.
- Tian Tian received an Asociación Española Contra el Cáncer - AECC (Spanish Association against Cancer) Investigator Award for research focused on NUT-midline carcinoma.
- We have generated and fully characterized (molecularly and clinically) a unique collection of 19 advanced cholangiocarcinoma patient-derived xenograft (PDX) models.
Horizons
- Characterize oxidized H3 in solid tumors and determine whether oxidized H3 peptide can be used as an inhibitor. If confirmed, this could be a new therapeutic strategy (and a start-up opportunity).
- Publish the data obtained from ER+ BC patients resistant to hormone therapy and CDK4/6 inhibitors in a scientific journal.
- Expand the number of CCA PDXs, and characterize our Cas9-expressing CCA cell lines (negative/positive screening) with different inhibitors (PARPi, BETi, IDH1i, FGFRi).
- Establish tumoroids from CCA human biopsies and isolate expanded tumor-infiltrating lymphocites (TILs) from the same CCA patients to co-culture with tumoroids. This can be used to test the efficacy of immune checkpoint inhibitors (alone or in combination with other treatments).
- Characterize the different cell populations in CCA tumor samples by single-cell transcriptomics.
- Publish a manuscript on the NMC project (in prep.), and generate further PDXs from NMC patients. Since NMC is rare with a low engraftment rate, we will need several years to do so. To-date we have generated three.
PI paper pick 2021
- Serra-Bardenys G, Peiró S. Enzymatic lysine oxidation as a posttranslational modification. FEBS J. 2021 Sep 18.
Projects
- Identificación y caracterización de nuevos elementos reguladores durante la adquisición de competencias metastásicas en un modelo de transición epitelio-mesénquima y en tumores de mama triple-negativos. Funding: Institute of Health Carlos III – ISCIII (FIS). 2019–2022.
- Epigenetic Landscape Characterization of Cholangiocarcinomas. Funding: Fundació Marató TV3. 2020–2023.
- Molecular Characterization of mutant IDH1 inhibition in Cholangiocarcinomas. Funding: LOXO Oncology at Lilly. 2021–2024.
- Preclinical study of BGB-290 in cholangiocarcinoma models. Funding: Beigene. 2018–2021.
Full list of publications 2021
- Serra-Bardenys G, Peiró S. Enzymatic lysine oxidation as a posttranslational modification. FEBS J. 2021 Sep 18.
Experimental Therapeutics Group
Violeta Serra
Principal Investigator
Biosketch
Biosketch Violeta Serra
Violeta Serra obtained her PhD in 2001 in the field of cellular aging and telomeres from Newcastle University (UK). She gained a Marie Curie Postdoctoral Fellowship, to study cancer chemotherapy resistance at the Humboldt University, Berlin (Germany). In 2004 she moved to the Spanish National Cancer Research Center (CNIO, Madrid), where she pursued her interest in understanding the role of intracellular kinases as potential drug targets in cancer.
In 2006 Violeta joined José Baselga’s group at the Vall d’Hebron Institute of Oncology (VHIO), to explore the mode of action and mechanisms of resistance to PI3K-pathway inhibitors. Her work has been pivotal in defining adaptive responses to these agents in breast cancer cells.
Since 2014 she has led VHIO´s Experimental Therapeutics Group, and continues to expand her research into targeted therapies in triple negative breast cancers – PARP inhibitors in particular.
To establish herself as an independent Principal Investigator, Violeta was awarded with two Instituto Salud Carlos III (ISCII) Project Grants, a Career Catalyst Research Grant from the Susan G. Komen Foundation and from the Breast Cancer Now Catalyst Program.
Violeta is the coordinator of a European project funded by the ERA PerMed program named RAD51predictand is a partner of the H2020 MESI-STRAT consortium.
She is also member of the American Association of Cancer Research (AACR), the European Association of Cancer Research, serves on the Editorial Board of Clinical Cancer Research, and is also an ad-hoc reviewer for multiple journals and Granting agencies.
Summary
Our group conducts bench-to-bedside preclinical research in breast cancer to advance insights into biomarkers of response to targeted therapies. To do so, we generate preclinical models including patient-derived xenografts (PDXs) and patient-derived cultures (PDCs) from breast cancer patient samples.
We have significantly contributed to the field of PI3K inhibitor resistance and continue to more deeply explore mechanisms of resistance to CDK4/6 inhibitors, FGFR inhibitors, AKT inhibitors and AR modulators (SARMs) in breast tumors.
Additionally, we are exploring the potential of a novel HER3-targeted antibody-drug conjugate (ADC) as a therapeutic strategy for advanced breast cancers that have developed resistance to the current standard of care treatments.
Using clinically relevant PDXs, we have provided data to further support that the loss of G1-cell cycle checkpoint control, such as mutation/loss of RB1 or CCND1- amplification, is associated with the lack of response to CDK4/6 blockade in estrogen receptor-positive breast cancer. Additionally, we generated a collection of PDXs containing FGFR amplification to study biomarkers of sensitivity to FGFR inhibitors; both pan-FGFR1-4 and Multi-targeted Tyrosine Kinase Inhibitors (MTKIs).
Encouraged by the early success of DNA damage repair inhibitors in germline BRCA1/2 mutated tumors, we initiated a project aimed at identifying response biomarkers of PARP inhibitors (PARPi) as well as other DNA damage repair inhibitors including those targeting WEE1 or ATR.
Our studies underpin the capacity of germline BRCA mutant tumors to recover DNA repair functionality and develop resistance to PARPi. We have developed an assay, the RAD51 test, which accurately identifies germline BRCA tumors that have restored DNA repair functionality and become resistant to these drugs. Importantly, this test also identifies tumors that are sensitive to PARPi through its alterations in DNA repair by homologous recombination beyond the germline BRCA condition. We filed a patent (EU application in 2017 and PCT in 2018), and we are currently validating the use of this test in tumor samples from breast, ovarian, and prostate cancer patients.
Finally, we are also investigating the effects of PARPi on the tumor immune environment. DNA repair-deficient tumors accumulate cytosolic DNA, which can elicit an innate immune signal (the STING pathway) and upregulate interferon-related genes, leading to lymphocytic infiltration and PD-L1 expression. We are testing the hypothesis that treatment of DNA repair-deficient tumors with PARPi elicits a DNA damage response, resulting in upregulation of PD-L1 that might limit the antitumor immune-mediated cytotoxicity by lymphocytes, but sensitizes to anti-PD-L1 treatments.
Our group works closely together with Cristina Saura’s Breast Cancer Group, and Judith Balmaña’s Hereditary Cancer Genetics Group. Reflective of VHIO’s purely multidisciplinary and translational approach, our research is also carried out in collaboration with other groups including VHIO’s Molecular Oncology Group, and Oncology Data Science – OdysSey Group, directed by Paolo Nuciforo and Rodrigo Dienstmann, respectively.
Our team has significantly advanced insights into the mode of action of novel targeted therapies, identified new response biomarkers, and developed a biomarker-based assay with potential clinical application. We have also demonstrated the efficacy of hypothesis-based drug combinations.
Strategic goals
- Develop predictive biomarkers of targeted treatments in ER+ and triple negative breast cancers, including inhibitors directed against the DNA damage repair protein PARP as well as signaling/cell cycle kinases (CDK4/6, PI3K/AKT or FGFR).
- Explore novel treatment combinations for ER+ and triple negative breast cancers.
- Contribute to personalized medicine by developing a diagnostic test to better guide treatment strategies based on PARP inhibitors.
- Establishing patient tumor-derived breast cancer preclinical models to explore hypothesis-based combinatorial therapies.
Highlights
- Our group has contributed towards achieving a better understanding of the mechanisms underlying sensitivity to AKT inhibitors in breast cancer, as well as the clinical utility of diagnostic tools based on the identification of DNA repair deficiency.
- We have obtained funding from the "La Caixa" Foundation, Asociación Española Contra el Cáncer – AECC, Agència de Gestió d'Ajuts Universitaris i de Recerca – AGAUR (Agency for Management of University and Research Grants), and the Instituto de Salud Carlos III – ISCIII (Carlos III Health Institute), to develop a pre-commercial prototype of the RAD51 test for implementation into the Vall d’Hebron University Hospital’s (HUVH) diagnostic programs.
- We have established a panel of over one hundred ER+ and triple negative breast cancer PDXs, mainly from the metastatic setting. We particularly focus on models that recapitulate progression on CDK4/6 inhibitors, and BRCA1/2-associated tumors.
Horizons
- Validation of the homologous repair deficiency (HRD) biomarker based on the detection of RAD51 in retrospective and prospective clinical trials.
- Optimization of the RAD51 assay to be used in liquid biopsies (CTCs in blood) and automatization of the staining and image analysis of the test to facilitate its future implementation in the clinic.
- Identification of resistance mechanisms to CDK4/6 inhibitors and study of novel therapeutic strategies, including AR modulators or antibody-drug conjugates (ADCs) for the treatment of advanced breast cancer. Based on these results, new patient stratification and therapeutic algorithms will be proposed for improving the response of patients who do not derive clinical benefit from current therapies.
- Unveil genetic and epigenetic mechanisms of acquired resistance to PARP inhibitors (PARPi) in hereditary BRCA1/2 breast cancer and beyond; by other HRR alterations.
- Dissect the role of the STING pathway in BRCA mutated tumors and explore the combination of PARPi and anti-PD-L1 therapies.
- Continue expanding the panel of patient tumor-derived breast cancer models to investigate hypothesis-based, clinically-applicable therapy combinations in breast cancer aimed at overcoming resistance to both anti-estrogen therapy and PARPi.
PI paper pick 2021
- Sánchez-Guixé M, Hierro C, Jiménez J, Viaplana C, Villacampa G, Monelli E, Brasó-Maristany F, Ogbah Z, Parés M, Guzmán M, Grueso J, Rodríguez O, Oliveira M, Azaro A, Garralda E, Tabernero J, Casanovas O, Scaltriti M, Prat A, Dienstmann R, Nuciforo P, Saura C, Graupera M, Vivancos A, Rodon J, Serra V. High FGFR1-4 mRNA Expression Levels Correlate with Response to Selective FGFR Inhibitors in Breast Cancer. Clin Cancer Res. 2022 Jan 1;28(1):137-149. Epub 2021 Sep 30.
- Llop-Guevara A, Loibl S, Villacampa G, Vladimirova V, Schneeweiss A, Karn T, Zahm DM, Herencia-Ropero A, Jank P, van Mackelenbergh M, Fasching PA, Marmé F, Stickeler E, Schem C, Dienstmann R, Florian S, Nekljudova V, Balmaña J, Hahnen E, Denkert C, Serra V. Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial. Ann Oncol. 2021 Dec;32(12):1590-1596.
- Carreira S, Porta N, Arce-Gallego S, Seed G, Llop-Guevara A, Bianchini D, Rescigno P, Paschalis A, Bertan C, Baker C, Goodall J, Miranda S, Riisnaes R, Figueiredo I, Ferreira A, Pereira R, Crespo M, Gurel B, Nava Rodrigues D, Pettitt SJ, Yuan W, Serra V, Rekowski J, Lord CJ, Hall E, Mateo J, de Bono JS. Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Cancer Discov. 2021 Nov;11(11):2812-2827.
- Gris-Oliver A, Ibrahim YH, Rivas MA, García-García C, Sánchez-Guixé M, Ruiz-Pace F, Viaplana C, Pérez-García JM, Llombart-Cussac A, Grueso J, Parés M, Guzmán M, Rodríguez O, Anton P, Cozar P, Calvo MT, Bruna A, Arribas J, Caldas C, Dienstmann R, Nuciforo P, Oliveira M, Cortés J, Serra V. PI3K activation promotes resistance to eribulin in HER2-negative breast cancer. Br J Cancer. 2021 Apr;124(9):1581-1591.
AWARDS AND RECOGNITION 2021
- Award from the Metastatic Breast Cancer Association: III Premio M. Chiara Giorgetti, 2021.
Projects
- Understanding CDK4/6i and SERD resistance in metastatic ER+ breast cancer using patient samples and PDXs.
Funding Agency: AstraZeneca.
Principal Investigators: Cristina Saura and Violeta Serra.
Duration: 2022-2023. - Inter-observer validation of the RAD51 test in samples from VIOLETTE and in an “intent-to-test” population from VHUH patients with breast, ovarian, prostate and pancreatic tumors. Integration with non-commercial genetic/genomic tests.
Funding Agency: AstraZeneca.
Principal Investigator: Violeta Serra.
Duration: 2022-2023.
- PARPiPRED, diagnostic test that facilitates personalized medicine in cancer treatment (2019PROD00045).Funding Agency: AGAUR-Producte.Principal Investigator: Violeta Serra.Duration: 2020-2021.
- Developing new therapeutic strategies to overcome CDK4/6 resistance in estrogen receptor positive breast cancer (PI20/00892).
Funding Agency: ISCIII.
Principal Investigators: Violeta Serra and Meritxell Bellet.
Duration: 2021-2023. - RAD51predict: Patient stratification based on DNA repair functionality for cancer precision medicine (ERAPERMED2019-215).
Funding Agency: ERA Net.
Coordinator: Violeta Serra.
Duration: 2020-2022. - Liquid biopsies for the identification of mechanisms of resistance to PARP inhibitors in BRCA1/2-associated cancers (654/C/2019).
Funding Agency: La Marató TV3.
Coordinator: Violeta Serra.
Duration: 2020-2022. - Modulation of androgen receptor signalling as a therapeutic strategy for estrogen receptor-positive metastatic breast cancer (2018NovPCC1291).
Funding Agency: Breast Cancer Now.
Principal Investigator: Violeta Serra.
Duration: 2019-2021.
FULL LIST OF PUBLICATIONS 2021
- High FGFR1-4 mRNA expression levels correlate with response to selective FGFR inhibitors in breast cancer. Sánchez-Guixé M, Hierro C, Jiménez J, Viaplana C, Villacampa G, Monelli E, Brasó-Maristany F, Ogbah Z, Parés M, Guzmán M, Grueso J, Rodriguez O, Oliveira M, Azaro A, Garralda E, Tabernero J, Casanovas O, Scaltriti M, Prat A, Dienstmann R, Nuciforo P, Saura C, Graupera M, Vivancos A, Rodon J, Serra V. Clin Cancer Res. 2022 Jan 1;28(1):137-149. doi: 10.1158/1078-0432.CCR-21-1810. PMID: 34593528.
- INK4 tumor suppressor proteins mediate resistance to CDK4/6 kinase inhibitors. Li Q, Jiang B, Guo J, Shao H, Del Priore IS, Chang Q, Kudo R, Li Z, Razavi P, Liu B, Boghossian AS, Rees MG, Ronan MM, Roth JA, Donovan KA, Palafox M, Reis-Filho JS, de Stanchina E, Fischer ES, Rosen N, Serra V, Koff A, Chodera JD, Gray NS, Chandarlapaty S. Cancer Discov. 2021 Sep 20:candisc.1726.2020. doi: 10.1158/2159-8290.CD-20-1726. PMID: 34544752.
- Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial. Llop-Guevara A, Loibl S, Villacampa G, Vladimirova V, Schneeweiss A, Karn T, Zahm DM, Herencia-Ropero A, Jank P, van Mackelenbergh M, Fasching PA, Marmé F, Stickeler E, Schem C, Dienstmann R, Florian S, Nekljudova V, Balmaña J, Hahnen E, Denkert C, Serra V. Ann Oncol. 2021 Sep 11:S0923-7534(21)04478-1. doi: 10.1016/j.annonc.2021.09.003. PMID: 34520831.
- Clinical consequences of BRCA2 hypomorphism. Castells-Roca L, Gutiérrez-Enríquez S, Bonache S, Bogliolo M, Carrasco E, Aza-Carmona M, Montalban G, Muñoz-Subirana N, Pujol R, Cruz C, Llop-Guevara A, Ramírez MJ, Saura C, Lasa A, Serra V, Diez O, Balmaña J, Surrallés J. NPJ Breast Cancer. 2021 Sep 9;7(1):117. doi: 10.1038/s41523-021-00322-9. PMID: 34504103.
- Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition. Aziz D, Portman N, Fernandez KJ, Lee C, Alexandrou S, Llop-Guevara A, Phan Z, Yong A, Wilkinson A, Sergio CM, Ferraro D, Etemadmoghadam D, Bowtell DD; kConFab Investigators, Serra V, Waring P, Lim E, Caldon CE. NPJ Breast Cancer. 2021 Aug 31;7(1):111. doi: 10.1038/s41523-021-00312-x. PMID: 34465787.
- Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Carreira S, Porta N, Arce-Gallego S, Seed G, Llop-Guevara A, Bianchini D, Rescigno P, Paschalis A, Bertan C, Baker C, Goodall J, Miranda S, Riisnaes R, Figueiredo I, Ferreira A, Pereira R, Crespo M, Gurel B, Nava Rodrigues D, Pettitt SJ, Yuan W, Serra V, Rekowski J, Lord CJ, Hall E, Mateo J, de Bono JS. Cancer Discov. 2021 May 27:candisc.0007.2021. doi: 10.1158/2159-8290.CD-21-0007. Online ahead of print. PMID: 34045297.
- Wright SCE, Vasilevski N, Serra V, Rodon J, Eichhorn PJA. Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity. Cancers (Basel). 2021 Mar 26;13(7):1538. doi: 10.3390/cancers13071538. PMID: 33810522.
- Gris-Oliver A, Ibrahim YH, Rivas MA, García-García C, Sánchez-Guixé M, Ruiz- Pace F, Viaplana C, Pérez-García JM, Llombart-Cussac A, Grueso J, Parés M, Guzmán M, Rodríguez O, Anton P, Cozar P, Calvo MT, Bruna A, Arribas J, Caldas C, Dienstmann R, Nuciforo P, Oliveira M, Cortés J, Serra V. PI3K activation promotes resistance to eribulin in HER2-negative breast cancer. Br J Cancer. 2021 Mar 15. doi: 10.1038/s41416-021-01293-1. PMID: 33723394
- Georgopoulou D, Callari M, Rueda OM, Shea A, Martin A, Giovannetti A, Qosaj F, Dariush A, Chin SF, Carnevalli LS, Provenzano E, Greenwood W, Lerda G, Esmaeilishirazifard E, O'Reilly M, Serra V, Bressan D; IMAXT Consortium, Mills GB, Ali HR, Cosulich SS, Hannon GJ, Bruna A, Caldas C. Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response. Nat Commun. 2021 Mar 31;12(1):1998. doi: 10.1038/s41467-021-22303-z. PMID: 33790302; PMCID: PMC8012607.
- Eikesdal HP, Yndestad S, Elzawahry A, Llop-Guevara A, Gilje B, Blix ES, Espelid H, Lundgren S, Geisler J, Vagstad G, Venizelos A, Minsaas L, Leirvaag B, Gudlaugsson EG, Vintermyr OK, Aase HS, Aas T, Balmaña J, Serra V, Janssen EAM, Knappskog S, Lønning PE. Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Ann Oncol. 2021 Feb;32(2):240-249. doi: 10.1016/j.annonc.2020.11.009. Epub 2020 Nov 24. PMID: 33242536.
- Woo XY, Giordano J, Srivastava A, Zhao ZM, Lloyd MW, de Bruijn R, Suh YS, Patidar R, Chen L, Scherer S, Bailey MH, Yang CH, Cortes-Sanchez E, Xi Y, Wang J, Wickramasinghe J, Kossenkov AV, Rebecca VW, Sun H, Mashl RJ, Davies SR, Jeon R, Frech C, Randjelovic J, Rosains J, Galimi F, Bertotti A, Lafferty A, O'Farrell AC, Modave E, Lambrechts D, Ter Brugge P, Serra V, Marangoni E, El Botty R, Kim H, Kim JI, Yang HK, Lee C, Dean DA 2nd, Davis-Dusenbery B, Evrard YA, Doroshow JH, Welm AL, Welm BE, Lewis MT, Fang B, Roth JA, Meric-Bernstam F, Herlyn M, Davies MA, Ding L, Li S, Govindan R, Isella C, Moscow JA, Trusolino L, Byrne AT, Jonkers J, Bult CJ, Medico E, Chuang JH; PDXNET Consortium; EurOPDX Consortium. Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts. Nat Genet. 2021 Jan;53(1):86-99. doi: 10.1038/s41588-020-00750-6. Epub 2021 Jan 7. PMID: 33414553.
Gene Expression & Cancer Group
Joan Seoane
Principal Investigator
Biosketch
Biosketch Joan Seoane
Upon completing his post-doctoral studies in 2004, Joan decided to establish his own group pursuing an independent research project. Since he believed that cancer can only be combated through combining basic and clinical research efforts, Joan sought to set up his laboratory as closely as possible to a clinical research unit in order to fluently interchange findings in basic research with the clinical ambit and hence carry out translational research. For this very reason, he chose to join a research institute linked to a hospital – the Vall d’Hebron Institute of Oncology (VHIO), which is both situated at the heart of the Vall d’Hebron University Hospital – one of the biggest hospitals in Spain, and also has a Medical Oncology Department with an outstanding clinical trial program and portfolio in solid tumors. VHIO therefore provided Joan with the optimal setting and environment through which to deliver on his objectives.
He was appointed as a Group Leader at VHIO and ICREA Research Professor in 2004, and decided to focus his research on glioblastoma as a model to study cancer. Specifically, Joan wanted to tackle one of the most important challenges in the treatment of cancer: tumor heterogeneity.
Cancer is a disease with two levels of heterogeneity, an intertumor heterogeneity (each patient has a different tumor) and an intratumor heterogeneity (cells within a tumor are different). Tumors from different patients are molecularly diverse and have different sensitivities to treatment. However, there is another level of complexity. Cells within a tumor are diverse with different genomic alterations or different states of differentiation. This has very important clinical implications since a treatment might target one cell type but not others – therefore being unable to cure.
Linked to the intratumoral heterogeneity concept, a subpopulation of undifferentiated cells with stem cell-like characteristics has been identified within the tumor mass. This pool of cells, called cancer-initiating cells (CICs) or cancer stem cells, are considered to be responsible for the initiation, recurrence and chemo- and radio-resistance of tumors. CICs are, therefore, crucial therapeutic targets and better understanding of the molecular mechanisms involved in this type of cells is still needed.
In order to study tumor heterogeneity, cancer must be studied as close as possible to the real tumor of the patient. In 2005, Joan set up a multidisciplinary team incorporating oncologists, neurosurgeons and pathologists. For the first time at the Vall d’Hebron University Hospital, he managed to establish a ‘circuit’ through which to obtain human specimens from the surgeons and pathologists to generate tumor models that recapitulate the characteristics of the human tumor of origin. Tumor samples were obtained 15 minutes after surgery and cell populations from the tumor such as CICs were studied.
Moreover, CICs are orthotopically inoculated in the brain of mice to generate tumors that recapitulate the characteristics of the original human tumor. Hence, Joan’s team regenerated patients’ tumors in mice to study the molecular characteristics of tumors and, more importantly, identify the optimal treatment tailored to the specificities of individual disease.
Using these models, Joan has generated important data in glioblastoma and cancer stem cells with important implications at the clinical level. He has three patents and an outstanding publication record with articles published in high impact journals including Cancer Cell, Nature Medicine, Cancer Discovery, and Nature Communications, among others, as corresponding author.
Joan’s team has identified therapeutic targets against glioblastoma; identified markers of response to treatment with anti-TGFβcompounds improving the design of clinical trials by providing markers to more precisely stratify patients; and developed novel strategies by liquid biopsies to characterize brain tumors.
This work epitomizes the essence of translational research.
Appointed as an ICREA Professor in 2004, Joan continues to serve as an Associate Professor of the Universitat Autònoma de Barcelona (UAB) – since 2008. He is a Member of the Executive Committee of the European Association for Cancer Research (EACR), as well as Member of the Neuro-oncology Committee of the Vall d’Hebron University Hospital (HUVH).
His contributions to the field have been recognized by various awards and honors including the Memorial Sloan Kettering Cancer Center (MSKCC) Research Fellow Award, and the Catalan Society of Biology Award. In 2007 Joan became an EMBO Young Investigator, and in 2009 he received both the Sabadell Bank Award and the Sociedad Española de Bioquímica y Biología Molecular Award. He was received a European Research Council (ERC) Starting Grant in 2008.
In 2011 he was appointed as Director of VHIO’s Translational Research Program, and in 2013 he was awarded with the Dr. Josef Steiner Cancer Research Award, also receiving the prestigious Doctores Diz Pintado National award as well as the Spanish periodical La Vanguardia´s prize for science in 2016.
Joan is also Founder of VHIO born spin-off Mosaic Biomedicals. Through this Company, one of his discoveries has already translated into anti-cancer agents that are being clinically tested in patients.
Summary
We study primary brain tumors and brain metastasis; some of the most aggressive of all cancers. Both glioblastoma and brain metastasis are dismal diseases with limited therapeutic options. Advancing progress in this field toward improving outcomes for these patients is therefore critical.
Our group is designing tools to monitor and characterize brain tumors, with specific focus on brain metastasis and central nervous system lymphomas. By analyzing immune cells in cerebrospinal fluid, we discovered that we could obtain predictive biomarkers of response to immunotherapy without having to perform a majorly invasive intracranial biopsy (Rubio-Perez et al. 2021). Moreover, we have shown that cell free circulating tumor DNA in cerebrospinal fluid facilitates the monitoring and early detection of tumor relapse in central nervous system lymphomas (Bobillo et al. 2021).
While no biomarker derived from liquid biopsy against these tumor types has yet been integrated into clinical practice, mounting evidence reported in the literature, including our findings, points to its efficacy in the real-time evaluation of malignant disease and potential to better inform and guide the therapeutic management of patients. Reflective of our work in the field, we were invited to help elaborate the EANO – ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with brain metastasis (Le Rhun et al. 2021). It has been a privilege for us to collaborate alongside other renowned scientists and clinicians specialized in brain metastasis to set out these European clinical guidelines for the management of this dismal disease.
We are as committed to advancing research into the role of the tumor microenvironment which, in the case of brain cancers, assumes a crucial role in cancer progression. Advancing insights into the tumor microenvironment promises powerful weaponry in combating cancer, regardless of heterogeneity.
By eliminating the niche where tumors reside and thrive should enable us to develop more effective anti-cancer compounds. In this respect, we have reported that the cytokine LIF assumes an essential role in the tumor microenvironment and is consequently a promising therapeutic target.
We are now testing a novel agent MSC-1 (now AZD0171), a LIF neutralizing antibody, developed by VHIO spin-off, Mosaic Biomedicals, founded by Joan Seoane in 2012. Mosaic Biomedicals was acquired by Medimmune/Astrazeneca in 2020. A phase II clinical trial (NCT04999969) to test MSC-1 initiated patient recruitment in 2021.
Strategic goals
- Identify new therapeutic targets against brain tumors and novel biomarkers to more precisely predict response to therapy.
- The study of intratumor heterogeneity.
- Investigate the tumor microenvironment.
- Develop methods for non-invasive molecular diagnosis through the study of circulating biomarkers.
- Generate patient-derived mouse models of brain cancers.
Highlights
- By scRNAseq analysis, we have discovered that the immune cells present in the cerebrospinal fluid of brain metastasis patients can provide biomarkers to predict response to immunotherapy (Rubio-Perez et al. 2021).
- We have participated in the elaboration of the EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis (Le Rhun et al. 2021).
- We discovered a parallelism between the inflammation occurring in SARS-CoV-2 placenta infection and cancer, and found that SARS-CoV-2 infection can impact neonatal outcome (Cribiù et al. 2021).
- A phase II clinical trial (NCT04999969) to test MSC-1(now AZD0171), initiated patient recruitment in 2021.This novel compound was designed and developed by the VHIO born spin-off, Mosaic Biomedicals, founded by Joan Seoane in 2012. Mosaic Biomedicals was acquired by Medimmune/Astrazeneca in 2020.
Horizons
- Identify novel therapeutic targets against brain tumors.
- Advance insights into the brain tumor microenvironment.
- Develop and translate methods for the non-invasive characterization of brain tumors (liquid biopsy) into clinical practice.
PI paper pick 2021
- Rubio-Perez C, Planas-Rigol E, Trincado JL, Bonfill-Teixidor E, Arias A, Marchese D, Moutinho C, Serna G, Pedrosa L, Iurlaro R, Martínez-Ricarte F, Escudero L, Cordero E, Cicuendez M, Ruiz S, Parra G, Nuciforo P, Gonzalez J, Pineda E, Sahuquillo J, Tabernero J, Heyn H, Seoane J. Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment. Nat Commun. 2021 Mar 8;12(1):1503.
- Cribiù FM, Erra R, Pugni L, Rubio-Perez C, Alonso L, Simonetti S, Croci GA, Serna G, Ronchi A, Pietrasanta C, Lunghi G, Fagnani AM, Piñana M, Matter M, Tzankov A, Terracciano L, Anton A, Ferrazzi E, Ferrero S, Iurlaro E, Seoane J, Nuciforo P. Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission. J Clin Invest. 2021 Mar 15;131(6):e145427.
- Bobillo S, Crespo M, Escudero L, Mayor R, Raheja P, Carpio C, Rubio-Perez C, Tazón-Vega B, Palacio C, Carabia J, Jiménez I, Nieto JC, Montoro J, Martínez-Ricarte F, Castellvi J, Simó M, Puigdefàbregas L, Abrisqueta P, Bosch F, Seoane J. Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B-cell lymphomas. Haematologica. 2021 Feb 1;106(2):513-521.
- Le Rhun E, Guckenberger M, Smits M, Dummer R, Bachelot T, Sahm F, Galldiks N, de Azambuja E, Berghoff AS, Metellus P, Peters S, Hong YK, Winkler F, Schadendorf D, van den Bent M, Seoane J, Stahel R, Minniti G, Wesseling P, Weller M, Preusser M; EANO Executive Board and ESMO Guidelines Committee. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. 2021 Nov;32(11):1332-1347.
Projects
- Grantor: ISCIII-PFIS.
Title: Estudio del microambiente inmunosupresor del tumor cerebral. Project Reference: PI19/00318.
Role in the Project: Principal Investigator.
Duration: |2020-2022. - Grantor: Fundación ARECES.
Title: Identification of novel immunotherapeutic targets in lung and melanoma brain metastases. Role in the Project: Principal Investigator.
Duraton: 2019-2022. - Grantor: ISCIII-PFIS.
Title: Contrato predoctoral de formación en investigación en salud.
Project Reference: FI17/00345.
Role in the Project: Principal investigator.
Duration: 2018-2021. - Grantor: Fundación Científica de la AECC.
Title: Study of the molecular mechanisms involved in primary (glioblastoma) and secondary (metastasis) brain tumors to identify novel therapeutic targets and anti-cancer agents, biomarkers to select treatments and novel non-invasive methods for molecular diagnosis.
Project Reference: GCTRA16015SEDA.
Role in the Project: Principal Investigator.
Duration: 2017-2022.
FULL LIST OF PUBLICATIONS 2021
- Gulley JL, Schlom J, Barcellos-Hoff MH, Wang XJ, Seoane J, Audhuy F, Lan Y, Dussault I, Moustakas A. Dual inhibition of TGF-β and PD-L1: a novel approach to cancer treatment. Mol Oncol. 2021 Dec 1. Epub ahead of print.
- Nieto P, Elosua-Bayes M, Trincado JL, Marchese D, Massoni-Badosa R, Salvany M, Henriques A, Nieto J, Aguilar-Fernández S, Mereu E, Moutinho C, Ruiz S, Lorden P, Chin VT, Kaczorowski D, Chan CL, Gallagher R, Chou A, Planas-Rigol E, Rubio-Perez C, Gut I, Piulats JM, Seoane J, Powell JE, Batlle E, Heyn H. A single-cell tumor immune atlas for precision oncology. Genome Res. 2021 Oct;31(10):1913-1926.
- Le Rhun E, Guckenberger M, Smits M, Dummer R, Bachelot T, Sahm F, Galldiks N, de Azambuja E, Berghoff AS, Metellus P, Peters S, Hong YK, Winkler F, Schadendorf D, van den Bent M, Seoane J, Stahel R, Minniti G, Wesseling P, Weller M, Preusser M; EANO Executive Board and ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. EANO-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up of patients with brain metastasis from solid tumours. Ann Oncol. 2021 Nov;32(11):1332-1347.
- Escudero L, Martínez-Ricarte F, Seoane J. ctDNA-Based Liquid Biopsy of Cerebrospinal Fluid in Brain Cancer. Cancers (Basel). 2021 Apr 21;13(9):1989.
- Rubio-Perez C, Planas-Rigol E, Trincado JL, Bonfill-Teixidor E, Arias A, Marchese D, Moutinho C, Serna G, Pedrosa L, Iurlaro R, Martínez-Ricarte F, Escudero L, Cordero E, Cicuendez M, Ruiz S, Parra G, Nuciforo P, Gonzalez J, Pineda E, Sahuquillo J, Tabernero J, Heyn H, Seoane J. Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment. Nat Commun. 2021 Mar 8;12(1):1503.
- Cribiù FM, Erra R, Pugni L, Rubio-Perez C, Alonso L, Simonetti S, Croci GA, Serna G, Ronchi A, Pietrasanta C, Lunghi G, Fagnani AM, Piñana M, Matter M, Tzankov A, Terracciano L, Anton A, Ferrazzi E, Ferrero S, Iurlaro E, Seoane J*, Nuciforo P*. Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission. J Clin Invest. 2021 Mar 15;131(6):e145427. (*co-corresponding authors).
- Bobillo S, Crespo M, Escudero L, Mayor R, Raheja P, Carpio C, Rubio-Perez C, Tazón-Vega B, Palacio C, Carabia J, Jiménez I, Nieto JC, Montoro J, Martínez-Ricarte F, Castellví J, Simó M, Puigdefàbregas L, Abrisqueta P, Bosch F, Seoane J. Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B-cell lymphomas. Haematologica. 2021; 106(2):513-521.
- Puyol M, Seoane J, Aguilar E, Vozza LB, Orbe I, Crawford KH, Fernández A, Bray F, Johnson SE, Gopal S. WORLD CANCER RESEARCH DAY: A Call to Action for a Coordinated International Research Effort to Prevent, Diagnose, and Treat Cancer. Clin Cancer Res. 2021 Feb 15;27(4):963-966.
- Ligero Hernández M, Garcia Ruiz A, Viaplana C, Villacampa Javierre G, Raciti MV, Landa J, Matos I, Martin Liberal JJ, Ochoa de Olza M, Hierro C, Mateo J, Gonzalez Rodriguez M, Morales R, Suárez C, Rodon J, Élez E, Braña I, Muñoz Couselo E, Oaknin A, Fasani R, Nuciforo P, Gil D, Rubio-Pérez C, Seoane J, Felip E, Escobar M, Tabernero J, Carles J, Dienstmann R, Garralda E, Perez Lopez R. A CT-based Radiomics Signature Is Associated with Response to Immune Checkpoint Inhibitors in Advanced Solid Tumors. Radiology. 2021;299(1):109-119.
Growth Factors Group
Joaquín Arribas
Principal Investigator
Biosketch
Biosketch Joaquín Arribas
Joaquín Arribas completed his undergraduate studies in biochemistry at the Universidad Autónoma de Madrid in 1987, where he subsequently worked on the regulation of the catalytic activities of the proteasome and was awarded his PhD in Biology in 1991.
Supported by a fellowship from the Spanish Ministry of Education and Science, he joined the Memorial Sloan-Kettering Cancer Center, New York (USA), as a Postdoctoral Fellow to work with J. Massagué (1992-1996) on the proteolytic processing of transmembrane growth factors.
In 1997, he joined the Oncology Department of the Vall d'Hebron University Hospital (HUVH) in Barcelona as a Staff Scientist and he has since led VHIO's Growth Factors Group. In 2001, he was promoted to lead the Oncology Research Program and later in 2007, he was appointed as Research Professor of the Catalan Institution for Research and Advanced Studies (ICREA). Since 2010 he has served as Director of VHIO's Preclinical Research Program.
His research has been recognized through an EMBO Young Investigator Programme (YIP) Award, the Beckman Coulter Award for the Best Young Spanish Investigator in Biochemistry and Molecular Biology, and grants from the Breast Cancer Research Foundation (BCRF) and the Spanish Association Against Cancer (AECC).
Joaquín is member of the Spanish and American Societies of Biochemistry and Molecular Biology as well as the American Association for Cancer Research (AACR). He has presided over the Committee for the evaluation of cancer research projects of the Instituto Salud Carlos III (ISCIII), and has served on the Executive Committee of the Red Territorial de Investigación Cooperativa en Cáncer (RTICC); the former main cancer research consortium in Spain for which he also coordinated the Breast Cancer Program.
In 2017, he was appointed as Director of the CIBERONC, the Spanish Cancer Research Consortium. In January 2020he was appointed as Research Director of the Mar Health Park/ Hospital del Mar Institute of Medical Research (PSMAR/IMIM), Barcelona.
Summary
2021 has been the second year of conciliation with the contingent limitations caused by COVID. However, our group has managed to continue working on all our research lines and we have produced significant results.
We have advanced insights into new mechanisms of resistance to targeted therapies. Firstly, we have demonstrated the role of the transcription factor SLUG in resistance to therapies directed against the RAF-MEK1/2-ERK1/2 pathway in pancreatic cancer (Bilal et al. 2021) Secondly, we have described a novel mechanism of acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation (Arenas et al. 2021; Martínez-Sabadell et al. 2021).
Our group has also collaborated with VHIO’s Sarcoma Translational Research Group, directed by César Serrano, in the study of E3 ubiquitin ligase Atrogin-1 as a mediator of adaptative resistance to KIT-targeted inhibition in gastrointestinal stromal tumor (García-Valverde et al. 2021).
Other collaborations have led to the following discoveries reported this year:
1) DNA hypomethylating agent (HMA) treatment can directly modulate the anti-tumor response and effector function of CD8+ T cells (Loo Yau et al. 2021), 2) the genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively counteracted with MEK/ERK inhibitors (Smith E. et al. 2021), iii) CAF-derived NRG1 mediates trastuzumab resistance through HER3/AKT, which might be reverted by pertuzumab (Guardia et al. 2021), iv) RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer (Sanz-Moreno et al. 2021), and v) PI3K activation promotes resistance to eribulin in HER2-negative breast cancer (Gris-Oliver et al. 2021).
For all these studies published in 2021 see PI Paper Pick plus footnotes* below.
Regarding unpublished results:
In the generation and characterization of CARs against tumor specific antigens, we have produced a fourth-generation CAR T cell that has shown promising results in vitro and in vivo. Once we have validated its efficacy and safety, this therapy will be tested in a first phase clinical trial.
Our group has continued to pursue research into the role of senescent cells in tumor progression. We have obtained significant results on how this differs according to tumor stage. This project has received funding from the Breast Cancer Research Foundation (BCRF) for two years.
Ariadna Grinyo, a PhD student supported by a ”la Caixa” Foundation INPhINIT Doctoral Fellowship-Incoming, joined our group in 2021. Ariadna has previous experience as a researcher of immune response at the biotechnology company Integral Molecular in Philadelphia (PA, USA), and has started her thesis on the generation of fourth-generation CARs against solid tumors.
* García-Valverde A, Rosell J, Sayols S, Gómez-Peregrina D, Pilco-Janeta DF, Olivares-Rivas I, de Álava E, Maurel J, Rubió-Casadevall J, Esteve A, Gut M, Valverde C, Barretina J, Carles J, Demetri GD, Fletcher JA, Arribas J, Serrano C. E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor. Oncogene. 2021 Dec;40(48):6614-6626.
Smith AE, Ferraro E, Safonov A, Morales CB, Lahuerta EJA, Li Q, Kulick A, Ross D, Solit DB, de Stanchina E, Reis-Filho J, Rosen N, Arribas J, Razavi P, Chandarlapaty S. HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway. Nat Commun. 2021 Nov 18;12(1):6667.
Guardia C, Bianchini G, Arpí-LLucià O, Menendez S, Casadevall D, Galbardi B, Dugo M, Servitja S, Montero JC, Soria-Jiménez L, Sabbaghi M, Peña R, Madoz-Gúrpide J, Lloveras B, Lluch A, Eroles P, Arribas J, Pandiella A, Gianni L, Rojo F, Rovira A, Albanell J. Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer. Clin Cancer Res. 2021 Sep 15;27(18):5096-5108.
Sanz-Moreno A, Palomeras S, Pedersen K, Morancho B, Pascual T, Galván P, Benítez S, Gomez-Miragaya J, Ciscar M, Jimenez M, Pernas S, Petit A, Soler-Monsó MT, Viñas G, Alsaleem M, Rakha EA, Green AR, Santamaria PG, Mulder C, Lemeer S, Arribas J, Prat A, Puig T, Gonzalez-Suarez E. RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer. Breast Cancer Res. 2021 Mar 30;23(1):42.
Gris-Oliver A, Ibrahim YH, Rivas MA, García-García C, Sánchez-Guixé M, Ruiz-Pace F, Viaplana C, Pérez-García JM, Llombart-Cussac A, Grueso J, Parés M, Guzmán M, Rodríguez O, Anton P, Cozar P, Calvo MT, Bruna A, Arribas J, Caldas C, Dienstmann R, Nuciforo P, Oliveira M, Cortés J, Serra V. PI3K activation promotes resistance to eribulin in HER2-negative breast cancer. Br J Cancer. 2021 Apr;124(9):1581-1591.
Strategic goals
- Generation and characterization of CARs against tumor specific antigens.
- Development of an ADC against p95HER2.
- Determine the role of cellular senescence in breast cancer progression and treatment.
- Identification of new mechanisms of resistance to targeted therapies.
Highlights
- We have generated a next generation CAR T Cell that showed very promising results in in vitro and in vivo experiments.
- We have generated a new ADC against p95HER2 for potential use in combinatorial therapy.
- We obtained preliminary results showing differential role of cellular senescence in cancer according to the stage of tumor progression.
- We identified a novel mechanism of resistance to targeted therapies, involving INF-y.
Horizons
- To identify mechanisms of resistance to targeted therapies in pancreatic cancer.
- Develop novel methods to redirect lymphocytes against breast cancer.
- Improve the effect of antibody drug conjugates.
PI paper pick 2021
- Bilal F, Arenas EJ, Pedersen K, Martínez-Sabadell A, Nabet B, Guruceaga E, Vicent S, Tabernero J, Macarulla T, Arribas J. The Transcription Factor SLUG Uncouples Pancreatic Cancer Progression from the RAF-MEK1/2-ERK1/2 Pathway. Cancer Res. 2021 Jul 15;81(14):3849-3861.
- Arenas EJ, Martínez-Sabadell A, Rius Ruiz I, Román Alonso M, Escorihuela M, Luque A, Fajardo CA, Gros A, Klein C, Arribas J. Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation. Nat Commun. 2021 Feb 23;12(1):1237.
- Martínez-Sabadell A, Arenas EJ, Arribas J. IFNY Signaling in Natural and Therapy-Induced Antitumor Responses. Clin Cancer Res. 2021 Nov 16. doi: 10.1158/1078-0432.CCR-21-3226. Epub ahead of print.
- Loo Yau H, Bell E, Ettayebi I, de Almeida FC, Boukhaled GM, Shen SY, Allard D, Morancho B, Marhon SA, Ishak CA, Gonzaga IM, da Silva Medina T, Singhania R, Chakravarthy A, Chen R, Mehdipour P, Pommey S, Klein C, Amarante-Mendes GP, Roulois D, Arribas J, Stagg J, Brooks DG, De Carvalho DD. DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells. Mol Cell. 2021 Apr 1;81(7):1469-1483.e8.
Full list of Publications 2021
- Bilal F, Arenas EJ, Pedersen K, Martínez-Sabadell A, Nabet B, Guruceaga E, Vicent S, Tabernero J, Macarulla T, Arribas J. The Transcription Factor SLUG Uncouples Pancreatic Cancer Progression from the RAF-MEK1/2-ERK1/2 Pathway. Cancer Res. 2021 Jul 15;81(14):3849-3861.
- Arenas EJ, Martínez-Sabadell A, Rius Ruiz I, Román Alonso M, Escorihuela M, Luque A, Fajardo CA, Gros A, Klein C, Arribas J. Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation. Nat Commun. 2021 Feb 23;12(1):1237.
- Martínez-Sabadell A, Arenas EJ, Arribas J. IFNγ Signaling in Natural and Therapy-Induced Antitumor Responses. Clin Cancer Res. 2021 Nov 16. doi: 10.1158/1078-0432.CCR-21-3226. Epub ahead of print.
- Loo Yau H, Bell E, Ettayebi I, de Almeida FC, Boukhaled GM, Shen SY, Allard D, Morancho B, Marhon SA, Ishak CA, Gonzaga IM, da Silva Medina T, Singhania R, Chakravarthy A, Chen R, Mehdipour P, Pommey S, Klein C, Amarante-Mendes GP, Roulois D, Arribas J, Stagg J, Brooks DG, De Carvalho DD. DNA hypomethylating agents increase activation and cytolytic activity of CD8+T cells. Mol Cell. 2021 Apr 1;81(7):1469-1483.e8.
Projects
- Redirection of T cells against HER2-driven tumors.
Asociación Española Contra el Cáncer (AECC). Grupos Coordinados AECC 2019.
Coordinator: Joaquín Arribas.
2019-2024. - Immunotherapy against HER2 positive tumors. PI19/01181.
Instituto Salud Carlos III (ISCIII).
PI: Joaquín Arribas.
2020-2022. - Conjugados Anticuerpo-Droga contra HER2: Mecanismos de Resistencia y Combinaciones Terapéuticas.
Fundación Mutua Madrileña.
Co-PIs: Joaquín Arribas, Javier Cortés.
2018-2021. - Horizon 2020 call SC1-PM-02-2017. Consortium 14 Partners.
Coordinator: Annette Byrne.
PI: Joaquín Arribas.
2018-2023. - EDIReX: EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts. 731105.
Horizon 2020 call H2020-INFRAIA 2016-2017.
Consortium 19 Partners.
Coordinator: Enzo Medico.
PI: Joaquín Arribas.
2018-2022.
Models of Cancer Therapies Group
Laura Soucek
Principal Investigator
Biosketch
Biosketch Laura Soucek
Laura Soucek graduated “Cum Laude” in Biological Sciences at the University La Sapienza, Rome (Italy) in 1996, defending her thesis on MYC dimerization specificity. At the same University, she then worked on the design of a MYC inhibitor – Omomyc – and was awarded her PhD in Genetics and Molecular Biology in 2001.
That same year, supported by a fellowship from the Italian National Research Center (CNR), she joined the Comprehensive Cancer Center of the University of California San Francisco (UCSF, USA), where she worked until 2006 as a Postdoctoral Fellow on mouse models of MYC driven tumorigenesis under the mentorship of Gerard Evan.
In 2006 she was promoted as Assistant Researcher, the Pathology Department of the University of California San Francisco (UCSF), where she worked on pre-clinically validating MYC inhibition as an anti-cancer therapeutic strategy. During this time, she was awarded various prestigious prizes including the AACR Future Leaders, New Directions Award for outstanding early-career scientists in cancer research, and the Bear Necessities Pediatric Cancer Foundation Award.
Laura joined the Vall d´Hebron Institute of Oncology (VHIO), Barcelona, in 2011 as Principal Investigator to lead the Models of Cancer Therapies Group. In Spain her research has been recognized through a Miguel Servet Programme grant, FERO Foundation Fellowships, a grant for Emerging Research Group of Catalunya from the Agency for Management of University and Research Grants (AGAUR), a BBVA Foundation grant in Biomedicine, a Retos de Colaboración grant from the Spanish Ministry of Economy, Industry and Competitiveness and two awards from the Instituto de Salud Carlos III (Institute of Health Carlos III, ISCIII) for a FIS – Fondo de Investigación en Salud (Health Research Fund). At international level, she was also recipient of a Worldwide Cancer Research grant and a European Research Council (ERC – European Commission) Consolidator, as well as two Proof-of-Concept grants within the framework of the Horizon 2020 Program.
Laura is a Scientific Editor for the journal Cancer Discovery, Review Editor for Frontiers in Oncology - Molecular and Cellular Oncology, and Reviewer for Anti-cancer Drugs, BBA (Biochimica et Biophysica Acta), BioDrugs, BioEssays, Cancer Discovery, Cancer Immunology and Immunotherapy, Cancer Immunology Research, Cancer Research, Cancer Research Communications, Cancer Treatment Reviews, Cancers, Cell Chemical Biology, Cell Death & Disease, Clinical Cancer Research, Communications Biology, Current Pharmaceutical Design, Developmental Dynamics, Drug Discovery Today, E-Biomedicine, eLIFE, Frontiers in Cell and Developmental Biology, Frontiers in Oncology, Gastroenterology Research and Practice, GEN Biotechnology, Gut, International Journal of Biological Sciences, IJEP (International Journal of Experimental Pathology), Journal of Cellular Biochemistry (JCB), Journal of Experimental and Clinical Cancer Research, JoVE Peer Reviewed Scientific Video Journal – Methods and Protocols, Medicinal Research Reviews, Molecular Biology and Evolution, Molecular Biology Reports, Molecular Oncology, Molecules, Nature, Nature Cell Biology, Nature Communications, Nature Medicine, Oncogene, Oncogenesis, “Oncology” books iConcept Press Ltd, Oncotarget, Peptide Science, Plos One, Science Advances, Science Translational Medicine, Scientific Reports, Therapeutic Advances in Chronic Disease, Trends in Cancer, and Tumor Biology.
Laura was appointed as a Research Professor at the prestigious Catalan Institution for Research and Advanced Studies (ICREA) in 2014. That same year, together with Marie-Eve Beaulieu – formerly a Postdoctoral Fellow of her group – she co-founded the VHIO and ICREA spin-off company Peptomyc S.L. In 2015, she was also appointed as an Associate Professor at the Universitat Autònoma de Barcelona (UAB).
Laura is also a member of the directive Scientific Committee of VHIO as well as the FERO Foundation.
Summary
Our group focuses on the pleiotropic and ubiquitous MYC oncoprotein, whose deregulation is implicated in almost all human cancers. The technical challenges of targeting nuclear transcription factors such as MYC –and the concern regarding potential side effects– had until recently precluded any preclinical validation of MYC inhibition as a possible therapeutic strategy.
Over the past few years, we have demonstrated in several mouse models that MYC inhibition has a dramatic therapeutic impact across several tumor types, with very mild and reversible side effects in normal tissue.
Encouraged by our results in mice, we are now interested in developing viable, non-toxic pharmacological options for MYC targeting in the clinic. To do so, we created a spin-off company, Peptomyc S.L., for the development of MYC-inhibiting peptides for cancer therapy. Our laboratory, in partnership with Peptomyc, is currently validating our novel approach against notoriously difficult-to-treat cancers that are resistant to standard treatments and in dire need of new therapeutic avenues (i.e., KRAS-driven Non-Small Cell Lung Cancer, glioblastoma, and metastatic triple negative breast cancer). Notably, the first Omomyc-derived compound, OMO-103, entered clinical trials Phase I/IIa in May 2021.
Our group has continued to contribute to cancer research in general and, more specifically, as a leader in the MYC field, by (co) authoring articles and reviews, exploring new aspects of MYC biology in different pathologies and summarizing efforts to develop a clinically viable MYC inhibitor.
Strategic goals
- Preclinically validate novel therapeutic strategies against MYC in breast, brain, lung, neuroblastoma, melanoma, colorectal cancer, and multiple myeloma.
- Validate anti-MYC Omomyc-based cell penetrating mini-proteins for cancer therapy.
- Define the role of MYC in promoting cancer immune evasion and test the efficacy of MYC inhibitors and IO combination treatments in cancer treatment.
- Investigate how the MYC network functions in Max-defective gastrointestinal stromal tumors (GISTs) and Small-Cell Lung Cancer (SCLC) to define actionable targets to tackle these unmet clinical needs.
Highlights
- In 2021, Laura’s laboratory has continued to publish science of excellence. Amongst other manuscripts, they published an article in Life Science Alliance, pointing to the Wnt signaling receptor Fzd9 as an essential molecule for MYC-driven tumorigenesis in pancreatic islets, first authored by Mariano Zacarías-Fluck and Toni Jauset, a former PhD student from her lab.
- Alongside Sandra Martínez-Martín (a former postdoc in the lab now working at Peptomyc), Laura Soucek authored a review in Cancer Drug Resistance on MYC inhibitory strategies for the treatment of multiple myeloma.
- Jonathan Whitfield and Laura Soucek published a review in the Journal of Cell Biology summarizing the different strategies adopted thus far against MYC as well as drug development efforts aimed at targeting MYC. They also highlight the initiation of the clinical trial with OMO-103, the compound developed by Laura’s group and the VHIO and ICREA spin-off Peptomyc.
- Jonathan and Laura also co-edited the second edition of The Myc Gene: Methods and Protocols (Springer Protocols, Humana Press) and authored the introductory chapter entitled: An “-omycs” Toolbox to Work with MYC.
- Laura Soucek’s group has also co-authored papers in EMBO Journal and Blood Advances, thanks to collaborations with the groups of Bruno Amati and Roberto Chiarle, on non-specific and sequence-specific DNA binding in MYC-driven transcription, and BCL6 as a therapeutic target in Burkitt lymphoma, respectively.
- The lab received funding through the I+D+I en Líneas Estratégicas en colaboración público-privada program, from the Spanish Ministry of Science and Innovation. This project involves VHIO, Peptomyc (VHIO and ICREA spin-off), the Hospital 12 de Octubre (Madrid, Spain), and CIMA, and aims at using MYC inhibition to overcome immunotherapy resistance in KRAS-driven NSCLC with diverse mutational profiles.
Horizons
- Advance the validation of novel therapies for cancer treatment, in particular against the previously undruggable target MYC.
- Define the roles of MYC in promoting cancer immune evasion and in Max-null tumors, and identify potential actionable targets and therapeutic strategies in these contexts.
PI paper pick 2021
- Whitfield JR, Soucek L. The long journey to bring a Myc inhibitor to the clinic. J Cell Biol. 2021 Aug 2;220(8):e202103090.
- Zacarías-Fluck MF, Jauset T, Martínez-Martín S, Kaur J, Casacuberta-Serra S, Massó-Vallés D, Serrano Del Pozo E, Martín-Fernández G, González-Larreategui Í, López-Estévez S, Brown-Swigart L, Beaulieu ME, Whitfield JR, Madan B, Virshup DM, Evan GI, Soucek L. The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets. Life Sci Alliance. 2021 Mar 2;4(5):e201900490. Print 2021 May.
- Martínez-Martín S, Soucek L. MYC inhibitors in multiple myeloma. Cancer Drug Resist 2021;4:842-65.10.20517/cdr.2021.55.
- Whitfield J, Soucek L. An "-omycs" Toolbox to Work with MYC. Methods Mol Biol. 2021;2318:1-11
FULL LIST OF PUBLICATIONS 2021
- Pighi C, Cheong TC, Compagno M, Patrucco E, Arigoni M, Olivero M, Wang Q, López C, Bernhart SH, Grande BM, Poggio T, Langellotto F, Bonello L, Dall'Olio R, Martínez-Martín S, Molinaro L, Francia di Celle P, Whitfield JR, Soucek L, Voena C, Calogero RA, Morin RD, Staudt LM, Siebert R, Zamò A, Chiarle R. Frequent mutations of FBXO11 highlight BCL6 as a therapeutic target in Burkitt lymphoma. Blood Adv. 2021 Dec 14;5(23):5239-5257. doi: 10.1182/bloodadvances.2021005682.
- Martínez-Martín S, Soucek L. MYC inhibitors in multiple myeloma. Cancer Drug Resist2021;4:842-65.20517/cdr.2021.55. Review.
- Whitfield JR, Soucek L. The long journey to bring a Myc inhibitor to the clinic. J Cell Biol. 2021 Aug 2;220(8):e202103090. doi: 10.1083/jcb.202103090. Epub 2021 Jun 23.
- Whitfield J, Soucek L. An "-omycs" Toolbox to Work with MYC. Methods Mol Biol. 2021;2318:1-11. doi: 10.1007/978-1-0716-1476-1_1.
- Zacarías-Fluck MF, Jauset T, Martínez-Martín S, Kaur J, Casacuberta-Serra S, Massó-Vallés D, Serrano Del Pozo E, Martín-Fernández G, González-Larreategui Í, López-Estévez S, Brown-Swigart L, Beaulieu ME, Whitfield JR, Madan B, Virshup DM, Evan GI, Soucek L. The Wnt signaling receptor Fzd9 is essential for Myc-driven tumorigenesis in pancreatic islets. Life Sci Alliance. 2021 Mar 2;4(5):e201900490. doi: 10.26508/lsa.201900490. PMID: 33653688; PMCID: PMC8008953.
- Pellanda P, Dalsass M, Filipuzzi M, Loffreda A, Verrecchia A, Castillo Cano V, Thabussot H, Doni M, Morelli MJ, Soucek L, Kress T, Mazza D, Mapelli M, Beaulieu ME, Amati B, Sabò A. Integrated requirement of non-specific and sequence-specific DNA binding in Myc-driven transcription. EMBO J. 2021 May 17;40(10):e105464. doi: 10.15252/embj.2020105464. Epub 2021 Apr 1. PMID: 33792944; PMCID: PMC8126922.
Projects
- Instituto de Salud Carlos III: Proyectos FIS de Investigación en Salud.
Title: Validation of new anti-Myc therapy in Melanoma. 2020-2023.
PI: Laura Soucek
Awarded in 2019. - Fundació La Marató de TV3
Title: Overcoming immunotherapeutic resistance through Myc inhibition in KRas-driven NSCLC with diverse mutational landscape.
2020-2022.
Project Director: Laura Soucek. Co-participant: Silvestre Vicent Cambra. - Canadian Institutes of Health Research Grant
Title: Development of cancer therapies targeting Myc with cell penetrating b-HLH-LZ domains.
2018-2023.
Role: Co-applicant. - H2020 INFRAIA 2017
Title: EDIReX: EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts.
2017-2021.
Role: Co-applicant5. I+D+I en Líneas Estratégicas en colaboración público-privada, Spanish Ministry of Economy, Industry and Competitiveness. Title: Using MYC inhibition to overcome immunotherapy resistance in KRAS-driven NSCLC with diverse mutational profiles (MYCOMBIO).
2021-2024.
PI: Laura Soucek - Ph.D. Fellowships from FIS– Fondo de Investigación en Salud (Health Research Fund) and Ministerio de Educación y Formación Profesional (Spanish Ministry of Education and Professional Training) University Professorship Training (FPU), awarded to Fabio Giuntini and Íñigo Larreategui, respectively.
- Fundación BBVA
Institutional grant, the VHIO-BBVA Foundation’s Immunotherapy & Immunology Program (CAIMI).
Prostate Cancer Translational Research Group
Joaquin Mateo
Principal Investigator
Biosketch
Biosketch Joaquin Mateo
Joaquin Mateo is a physician-scientist focused in the development of new therapeutic strategies towards a more precise care of advanced prostate cancer patients.
Joaquin completed his Medical Degree at the Universitat de Barcelona and completed his specialist training in Medical Oncology at the Catalan Institute of Oncology (ICO). He joined the Drug Development Unit at the Institute of Cancer Research – Royal Marsden NHS Foundation Trust in 2011 for a two-year fellowship under the supervision of Johann de Bono and Stan Kaye, where he worked on first-in-man clinical trials of several PARP inhibitors and compounds targeting the PI3-AKT-mTOR pathway. From 2013, he progressively focused on the design and development of clinical trials for castration-resistant prostate cancer (CRPC), completing his PhD in Cancer Genomics at Johann de Bono’s laboratory at the Institute of Cancer Research (UK). Towards the end of 2017, he joined VHIO to launch a new research group focused on advanced prostate cancer, following a bench-to-bedside-and-back research approach.
His main interest centers on the integration of tumor molecular characterization data into real-time clinical decision-making for patients through multidisciplinary tumor boards, as reflected by his involvement in the setting up of the molecular tumor boards at the Drug Development Unit and Prostate Cancer Targeted Therapy Unit at The Royal Marsden.
Joaquin is currently Chair of the European Society for Medical Oncology’s (ESMO) Precision Medicine Working Group, and led the development of the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). First published in 2018, ESCAT is a classification system to implement genomic testing towards better guiding treatment decision making; in 2020, the group published the first Recommendations document from a medical society for the implementation of next-generation sequencing in clinical practice.
While completing his PhD in the University of London, in 2016, he received a Prostate Cancer Foundation Young Investigator Award to continue working on the development of PARP inhibitors, platinum-based therapies and companion predictive biomarkers for CRPC patients. Later, he received awards from the European Commission MSCA Fellowship program (2018) and the CRIS Cancer Foundation Clinical Talent Award program (2021).
His significant contribution to the field has already resulted in his (co) authorship of several manuscripts published in top-tier journals including The New England Journal of Medicine, Clinical Cancer Research, Cell, European Urology, and Cancer Discovery. He has received research funding from competitive grants from the Prostate Cancer Foundation, the US Department of Defense Medical Research Program, the Instituto de Salud Carlos III– Spanish Ministry of Science and Innovation, the Spanish Society for Medical Oncology (SEOM), Fundación FERO, and the European Commission’s H2020 research program. In 2020, he obtained one of the prestigious Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer) LAB Awards for emerging groups and he is part of the awarded consortium in the GRUPOS COORDINADOS-AECC 2021 call.
As Principal Investigator of VHIO’s Prostate Cancer Translational Research Group, Joaquin leads research aimed at translating prostate cancer genotypes into phenotypes and a clinically-relevant classification of disease. He also seeks to build a precision medicine core for prostate cancer patients in his clinical practice at the Vall d’Hebron University Hospital (HUVH).
Summary
Our research model follows a bench-to-bedside-and-back approach. We have set up a platform for acquiring longitudinal samples from advanced prostate cancer patients, both tumor tissue as well as liquid biopsies, that can be used to investigate the evolving features of the disease, but also to generate patient-derived laboratory models of advanced prostate cancer that we can leverage to investigate new therapeutic strategies at the bench.
Moreover, the launch of investigator-initiated clinical trials is central to our research strategy, as a platform for correlative studies that can optimize the drug development pathway for prostate cancer patients. At present, we are the central laboratory for two academic multi-center clinical trials, as well as serve as the national repository for the IRONMAN registry; an important international effort to build a large bank of clinical data and biospecimens from metastatic prostate cancer (mPC) patients.
We aim to integrate insights in molecular biology, genomics, transcriptomics, computational sciences and clinical data towards developing precision medicine strategies for prostate cancer patients. To this end, our team comprises biomedical scientists with expertise in cancer biology, genomics and transcriptomics, bioinformatics and liquid biopsy, as well as medical oncologists and clinical data managers.
One of our main lines of research is to decipher how prostate cancers adapt to exposure to systemic therapies, particularly androgen-targeting agents, with a particular focus on the cell cycle and DNA damage response regulation and the emergence of quiescent and senescent phenotypes that can drive drug resistance. By studying in-vitro and in-vivo models, including patient-derived xenografts (PDX) from the patients participating in our clinical studies, we aim to understand how to target emergent phenotypes through drug combinations. These studies are currently funded by grants from the Spanish Ministry of Health, Fundación FERO (FERO Foundation), Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer), as well as through collaborations with biopharmaceutical companies.
Our group also aims to pursue the molecular characterization of advanced prostate cancer, focusing on how tumors evolve in a heterogeneous manner as they become resistant to different treatments. We have therefore set up a genomics and transcriptomics platform in the lab to perform DNA and RNA profiling from patient biopsies. We are developing novel liquid biopsies assays that will enable us to study the disease though longitudinal samples. By exploiting publicly available genomics datasets from patients at different stages of disease, our computational scientists investigate how the genomic profile of disease changes over time. These studies are currently funded by grants from the US Department of Defense's (DoD) Congressionally Directed Medical Research Programs (CDMRP), the Spanish Ministry of Health, CRIS Cancer Foundation, AECC, Fundación FERO, and the ”la Caixa” Foundation.
Lastly, given that well-annotated correlative clinical data is crucial to establish the potential relevance of molecular data, our team maintains databases collecting outcome data for all patients who donate samples for our studies to perform subsequent correlative analysis.
To more rapidly advance the field, we believe in team science. We therefore participate in several different collaborations that pool resources and combine cross border expertise across several different research teams and groups.
In summary, our research integrates different modalities of data generated in the lab that can lead to the design of therapeutic interventions aimed at improving outcomes for prostate cancer patients.
Strategic goals
- To investigate correlations between patient molecular profiling and clinical outcome that can guide more precise prostate cancer treatment strategies.
- Study how prostate cancers adapt to therapy, with a focus on targeting emerging vulnerabilities to delay disease recurrence.
- Investigate tumor heterogeneity in response to therapy in preclinical and patient-derived xenograft models (PDX), as well as by interrogating patient biopsies.
- Develop new liquid biopsy tools that can be used to monitor tumor evolution.
- Apply computational pipelines towards investigating genomic signatures in prostate cancer.
- Development of academic clinical trials to validate in the clinic our laboratory results, and leveraging patient biopsies for correlative studies.
Highlights
- We serve as central sample repository for the IRONMAN Registry in Spain. This project is driven by academic team-science and collects clinical data and biospecimens for correlative analysis from patients with advanced prostate cancer. VHIO acts as the national lead for this project that has already enrolled >250 men with advanced prostate cancer in Spain and >2500 worldwide.
- We received the CRIS Cancer Foundation Clinical Talent Award, allowing us to expand our group with bioinformatics expertise to study genomic signatures in prostate cancer.
- Regarding our interest in tumor adaptation and therapy-induced senescence, our group participates in a consortium that was awarded with a Coordinated Groups grant by the Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer).
- In collaboration with the Urology, Oncology and Radiology teams at the Vall d’Hebron University Hospital (HUVH), we have generated PDX models from prostate cancer biopsies.
- We are conducting our first investigator-initiated clinical trial, a phase II study co-targeting AR and PARP in metastatic hormone-naïve prostate cancer, which is actively recruiting in 9 hospitals across Spain.
Horizons
- Build a platform for collaborative research, integrating clinical and genomics data.
- Develop genomics and transcriptomics assays, from both tumor tissue and liquid biopsies, to stratify prostate cancer accordingly to clinically-relevant signatures.
- Generate laboratory models from patients’ biopsies for the investigation of new therapeutic strategies.
- Validate genomic and transcriptomics signatures associated with DDR defects in prostate cancer.
PI paper pick 2021
- Casanova-Salas I, Athie A, Boutros PC, Del Re M, Miyamoto DT, Pienta KJ, Posadas EM, Sowalsky AG, Stenzl A, Wyatt AW, Mateo J. Quantitative and Qualitative Analysis of Blood-based Liquid Biopsies to Inform Clinical Decision-making in Prostate Cancer. Eur Urol. 2021 Jun;79(6):762-771.
- Neeb A, Herranz N, Arce-Gallego S, Miranda S, Buroni L, Yuan W, Athie A, Casals T, Carmichael J, Rodrigues DN, Gurel B, Rescigno P, Rekowski J, Welti J, Riisnaes R, Gil V, Ning J, Wagner V, Casanova-Salas I, Cordoba S, Castro N, Fenor de la Maza MD, Seed G, Chandran K, Ferreira A, Figueiredo I, Bertan C, Bianchini D, Aversa C, Paschalis A, Gonzalez M, Morales- Barrera R, Suarez C, Carles J, Swain A, Sharp A, Gil J, Serra V, Lord C, Carreira S, Mateo J, de Bono JS. Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors. Eur Urol. 2021 Feb;79(2):200-211.
- Carreira S, Porta N, Arce-Gallego S, Seed G, Llop-Guevara A, Bianchini D, Rescigno P, Paschalis A, Bertan C, Baker C, Goodall J, Miranda S, Riisnaes R, Figueiredo I, Ferreira A, Pereira R, Crespo M, Gurel B, Nava Rodrigues D, Pettitt SJ, Yuan W, Serra V, Rekowski J, Lord CJ, Hall E, Mateo J, de Bono JS. Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Cancer Discov. 2021 Nov;11(11):2812-2827.
- Westphalen B, Fine AD, Andre F, Ganesan S, Heinemann V, Rouleau E, Turnbull C, Garcia Palacios L, Lopez JA, Sokol ES, Mateo J. Pan-cancer Analysis of Homologous Recombination Repair-associated Gene Alterations and Genome-wide Loss of Heterozygosity Score. Clin Cancer Res. 2021 Nov 5:clincanres.2096.2021. Epub ahead of print.
FULL LIST OF PUBLICATIONS 2021
- Casanova-Salas I, Athie A, Boutros PC, Del Re M, Miyamoto DT, Pienta KJ, Posadas EM, Sowalsky AG, Stenzl A, Wyatt AW, Mateo J. Quantitative and Qualitative Analysis of Blood-based Liquid Biopsies to Inform Clinical Decision-making in Prostate Cancer. Eur Urol. 2021 Jun;79(6):762-771.
- Neeb A, Herranz N, Arce-Gallego S, Miranda S, Buroni L, Yuan W, Athie A, Casals T, Carmichael J, Rodrigues DN, Gurel B, Rescigno P, Rekowski J, Welti J, Riisnaes R, Gil V, Ning J, Wagner V, Casanova-Salas I, Cordoba S, Castro N, Fenor de la Maza MD, Seed G, Chandran K, Ferreira A, Figueiredo I, Bertan C, Bianchini D, Aversa C, Paschalis A, Gonzalez M, Morales- Barrera R, Suarez C, Carles J, Swain A, Sharp A, Gil J, Serra V, Lord C, Carreira S, Mateo J, de Bono JS. Advanced Prostate Cancer with ATM Loss: PARP and ATR Inhibitors. Eur Urol. 2021 Feb;79(2):200-211.
- Carreira S, Porta N, Arce-Gallego S, Seed G, Llop-Guevara A, Bianchini D, Rescigno P, Paschalis A, Bertan C, Baker C, Goodall J, Miranda S, Riisnaes R, Figueiredo I, Ferreira A, Pereira R, Crespo M, Gurel B, Nava Rodrigues D, Pettitt SJ, Yuan W, Serra V, Rekowski J, Lord CJ, Hall E, Mateo J, de Bono JS. Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Cancer Discov. 2021 Nov;11(11):2812-2827.
- Westphalen B, Fine AD, Andre F, Ganesan S, Heinemann V, Rouleau E, Turnbull C, Garcia Palacios L, Lopez JA, Sokol ES, Mateo J. Pan-cancer Analysis of Homologous Recombination Repair-associated Gene Alterations and Genome-wide Loss of Heterozygosity Score. Clin Cancer Res. 2021 Nov 5:clincanres.2096.2021. Epub ahead of print.
AWARDS AND RECOGNITION 2021
- CRIS Cancer Foundation Clinical Talent Award.
Projects
- Clinical Qualification of DNA Repair Defects as Biomarkers in Metastatic Prostate Cancer Using Integrated Genomics and Tissue-Based Functional Assays.
Grantor: US Department of Defense Congressionally-Directed Medical Research Program. - Co-targeting androgen receptor signalling and DNA damage repair for precision therapy in advanced prostate.
Grantor: European Commission H2020 Program. - Novel approaches to liquid biopsy in prostate cancer to inform precision medicine.
Grantor: FERO Foundation. - Leveraging the AR-DDR interaction in de-novo metastatic prostate cancer towards precision combination therapies with PARP inhibitors.
Grantor: AECC (Fundación Asociación Española contra el Cáncer). - Integrated analysis of blood circulating tumor signatures to monitor genomic evolution and therapy responses in advanced Prostate Cancer.
Grantor: ”la Caixa” - Exploiting senescence in a two-step approach to treat advanced Prostate Cancer.
Grantor: Instituto de Salud Carlos III (ISCIII). - Tumoral senescence induced by anti-cancer therapies constitutes a novel prognostic biomarker and a therapeutic target.
Grantor: AECC (Fundación Asociación Española contra el Cáncer). - Prostate Cancer Genomic Evolution and Signatures of DNA Damage Repair Deficiencies.
Grantor: CRIS Cancer Foundation.
Clinical Trials
- IRONMAN-ES: Estudio prospectivo observacional de parámetros clinicos y biomarcadores en cáncer de próstata avanzado en hospitales de España.
- ZZ-First: A Biomarker–Discovery Phase II Trial of Enzalutamide and Talazoparib (BMN 673) for the Treatment of Metastatic Hormone–Naïve Prostate Cancer.
Sarcoma Translational Research Group
César Serrano
Principal Investigator
Biosketch
Biosketch César Serrano
I seek to pursue my academic career as a physician scientist focused on sarcoma translational research, with an emphasis on the biological understanding of sarcomas towards advancing drug development. To this end, our clinical-translational program is devoted to unravelling the intrinsic mechanisms of sensitivity and resistance to anticancer agents through high-throughput genomic and transcriptome studies, as well as developing cross-cutting therapeutic strategies.
In previous studies performed during my subspecialty training in sarcomas, I performed translational research that involved 1) demonstrating the molecular basis for the failure of TKIs in GIST; 2) developing preclinical evidence for an innovative therapeutic strategy against disease heterogeneity based on rapid alternation of TKIs with complementary inhibitory activity pattern, and 3) translating these insights into a phase Ib/II clinical trial.
Since my return to VHIO, my laboratory’s focus has extended beyond kinase signal transduction research and, with equal emphasis, we participate in highthroughput NGS studies to ultimately better understand the critical biologic mechanisms that lead to the heterogeneous behavior observed in the clinic when using different therapeutic agents.
We are also dedicated to developing liquid biopsy in sarcoma. Additionally, our current whole genome and transcriptome studies center on deciphering novel mechanisms of resistance and therapeutic vulnerabilities, irrespective of KIT genotype. Our team also leads translational research to reveal the biological mechanisms behind metastatic GIST patients with a long-term response to imatinib.
Finally, my clinical activities as a Medical Oncologist involve sarcoma patient care and drug development, thus applying basic discovery from the lab to the clinic for the benefit of these patients. In 2020, I was involved in the international teams that led to the FDA approval of ripretinib and avapritinib in GIST patients.
Summary
Sarcoma encompasses >70 entities of mesenchymal origin, constituting 1-2% of all cancers. From a biological perspective, sarcomas can be classified into two broad categories: sarcomas driven by simple genetic alterations, such as translocations or specific activating mutations; and tumors with complex and unbalanced genomic aberrations. Both include diverse sarcoma subtypes often with profound differences in their molecular makeup, course of disease and therapeutic approach.
We focus on the study of sarcomas with oncogenic dependency on specific drivers of disease. Among these, gastrointestinal stromal tumor (GIST) is the most common malignant mesenchymal neoplasm and constitutes a paradigmatic model for studying oncogene addiction and identifying structural and functional mechanisms for drug response and resistance.
Ongoing efforts aim at achieving a deeper biological understanding of GIST and other sarcomas in order to advance drug development. The heterogeneity of mechanisms of resistance represents one of the major challenges in improving outcomes for these patients. We therefore seek to identify crucial molecules and signaling mechanisms in GIST biology that can serve as therapeutic vulnerabilities.
Our group also continues to validate a core set of molecules that are co-regulated by KIT downstream pathways and identified through extensive whole transcriptome studies across several clinically representative human GIST models.
We also perform high-throughput genomic and transcriptomic studies to decipher the evolving patterns of resistance in GIST throughout the course of disease, as well as investigate liquid biopsy in sarcoma to provide robust evidence that will help to more precisely guide treatment decisions by plasma sequencing. In addition, the GISTomics project, a European initiative driven by our group, aims to advance insights into the landscape of GIST evolution.
Beyond GIST, our group has initiated new lines of research focused on other sarcoma subtypes, including muscle-derived sarcomas (leiomyosarcoma and rhabdomyosarcoma), angiosarcoma, and liposarcoma. Functional precision medicine is a major focus of research in these neoplasms.
Our aim is to have a true clinical impact by improving the daily treatment and care of our patients. We are proud to report that our Sarcoma Multidisciplinary Unit has been designated as an Expert Sarcoma Center of the European Reference Network ERN-EURACAN, and thus constitutes an optimal setting for translating cancer discovery into clinical benefits.
Strategic goals
- Identification of critical molecular mediators of oncogenic signaling in sarcomas.
- Characterization of response and resistance mechanisms to targeted therapies in sarcomas.
- Preclinical modelling and validation of therapeutic strategies to translate at the clinical level.
- Clinical drug development in sarcomas across phase I to phase III clinical trials.
Highlights
- Our group leads high-level studies towards the clinical implementation of liquid biopsy in GIST patients.
- We have been awarded by the Asociación Española Contra el Cáncer - AECC (Spanish Association Against Cancer) Senior Clinician Program to study the evolutionary landscape of resistance in GIST.
- César Serrano has been part of the international research teams whose work has led to the approval of ripretinib and avapritinib for the treatment of GIST patients.
- Our group is fully committed to generating laboratory models from most sarcoma subtypes thanks to the support received from patients through the #SarcModel initiative.
Horizons
- To develop E3 Ubiquitin ligase inhibitors as a salvage mechanism to boost TKI-induced apoptosis.
- Decipher novel patterns of resistance in TKI-refractory GIST.
- Pursue ctDNA implementation in GIST to guide clinical decisions.
- Preclinical and clinical drug development of novel compounds and/or combinations to transfer to the clinic.
PI paper pick 2021
- García-Valverde A, Rosell J, Sayols S, Gómez-Peregrina D, Pilco-Janeta DF, Olivares-Rivas I, de Álava E, Maurel J, Rubió-Casadevall J, Esteve A, Gut M, Valverde C, Barretina J, Carles J, Demetri GD, Fletcher JA, Arribas J, Serrano C. E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor. Oncogene. 2021 Dec;40(48):6614-6626.
- Bauer S, Heinrich MC, George S, Zalcberg JR, Serrano C, Gelderblom H, Jones RL, Attia S, D'Amato G, Chi P, Reichardt P, Meade J, Su Y, Ruiz-Soto R, Blay JY, von Mehren M, Schöffski P. Clinical Activity of Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumor Harboring Heterogeneous KIT/PDGFRA Mutations in the Phase III INVICTUS Study. Clin Cancer Res. 2021 Dec 1;27(23):6333-6342.
- Lostes-Bardaji MJ, García-Illescas D, Valverde C, Serrano C. Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward. Ther Adv Med Oncol. 2021 Jan 7;13:1758835920986498.
- Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, Schöffski P, Cassier PA, Mir O, Chawla SP, Eskens FALM, Rutkowski P, Tap WD, Zhou T, Roche M, Bauer S. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021 Mar;145:132-142.
FULL LIST OF PUBLICATIONS 2021
- Bauer S, Heinrich MC, George S, Zalcberg JR, Serrano C, Gelderblom H, Jones RL, Attia S, D'Amato G, Chi P, Reichardt P, Meade J, Su Y, Ruiz-Soto R, Blay JY, von Mehren M, Schöffski P. Clinical Activity of Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumor Harboring Heterogeneous KIT/PDGFRA Mutations in the Phase III INVICTUS Study. Clin Cancer Res. 2021 Dec 1;27(23):6333-6342.
- García-Valverde A, Rosell J, Sayols S, Gómez-Peregrina D, Pilco-Janeta DF, Olivares-Rivas I, de Álava E, Maurel J, Rubió-Casadevall J, Esteve A, Gut M, Valverde C, Barretina J, Carles J, Demetri GD, Fletcher JA, Arribas J, Serrano C. E3 ubiquitin ligase Atrogin-1 mediates adaptive resistance to KIT-targeted inhibition in gastrointestinal stromal tumor. Oncogene. 2021 Dec;40(48):6614-6626.
- Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, Schöffski P, Cassier PA, Mir O, Chawla SP, Eskens FALM, Rutkowski P, Tap WD, Zhou T, Roche M, Bauer S. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021 Mar;145:132-142.
- Lostes-Bardaji MJ, García-Illescas D, Valverde C, Serrano C. Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward. Ther Adv Med Oncol. 2021 Jan 7;13:1758835920986498.
- Gómez-Peregrina D, García-Valverde A, Pilco-Janeta D, Serrano C. Liquid Biopsy in Gastrointestinal Stromal Tumors: Ready for Prime Time? Curr Treat Options Oncol. 2021 Feb 27;22(4):32.
- George S, Jones RL, Bauer S, Kang YK, Schöffski P, Eskens F, Mir O, Cassier PA, Serrano C, Tap WD, Trent J, Rutkowski P, Patel S, Chawla SP, Meiri E, Gordon M, Zhou T, Roche M, Heinrich MC, von Mehren M. Avapritinib in Patients With Advanced Gastrointestinal Stromal Tumors Following at Least Three Prior Lines of Therapy. Oncologist. 2021 Apr;26(4):e639-e649.
- Zalcberg JR, Heinrich MC, George S, Bauer S, Schöffski P, Serrano C, Gelderblom H, Jones RL, Attia S, D'Amato G, Chi P, Reichardt P, Somaiah N, Meade J, Reichert V, Shi K, Sherman ML, Ruiz-Soto R, von Mehren M, Blay JY. Clinical Benefit of Ripretinib Dose Escalation After Disease Progression in Advanced Gastrointestinal Stromal Tumor: An Analysis of the INVICTUS Study. Oncologist. 2021 Nov;26(11):e2053-e2060.
- Joseph CP, Abaricia SN, Angelis MA, Polson K, Jones RL, Kang YK, Riedel RF, Schöffski P, Serrano C, Trent J, Tetzlaff ED, Si TD, Zhou T, Doyle A, Bauer S, Roche M, Havnaer T. Optimal Avapritinib Treatment Strategies for Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumors. Oncologist. 2021 Apr;26(4):e622-e631.
- Ravegnini G, Serrano C, Ricci R, Zhang Q, Terrenato I, Graziosi A, Valori G, Landolfi S, Hrelia P, Angelini S. miRNA landscape in primary tumors and matched metastases in gastrointestinal stromal tumors. Epigenomics. 2021 Mar;13(5):369-377.
- Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, Schöffski P, Cassier PA, Mir O, Chawla SP, Eskens FALM, Rutkowski P, Tap WD, Zhou T, Roche M, Bauer S. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021 Mar;145:132-142.
- Pilco-Janeta DF, García-Valverde A, Gomez-Peregrina D, Serrano C. Emerging drugs for the treatment of gastrointestinal stromal tumors. Expert Opin Emerg Drugs. 2021 Mar;26(1):53-62.
- Serrano C. New treatments in advanced gastrointestinal stromal tumor. Curr Opin Oncol. 2021 Jul 1;33(4):323-328.
AWARDS AND RECOGNITION 2021
- In 2021, César Serrano was awarded with the Ramiro Carregal Prize for Emerging Talents in Oncology Research, 2nd edition.
- César Serrano was appointed as a new Member of the European Society of Medical Oncology’s (ESMO) Sarcoma Faculty in 2021.
- He also joined the Spanish Society of Medical Oncology’s (SEOM) Executive Board (2021-2023).
Projects
- Determinantes clínicos y moleculares de respuesta y progresión a la inhibición de KIT en pacientes con tumores del estroma gastrointestinal (GIST) con respuesta prolongada a Imatinib. Grupo Español de Investigación en Sarcomas – GEIS (Spanish Group of Sarcoma Research). 2017-2022.
- Analysis of concurrent KIT and PI3K signaling inhibition as fron-line treatment in GIST in in vivo Bayer HealthCare 2017-2022.
- Determinantes clínicos y moleculares de respuesta y progresión a la inhibición de KIT en pacientes con tumores del estroma gastrointestinal (GIST) con respuesta prolongada a Imatinib Grupo Español de Investigación en Sarcomas – GEIS (Spanish Group of Sarcoma Research.) 2017-2022.
- Caracterización del potencial predictivo y terapéutico del FBXO32 como mediador crítico de la señalización oncogénica de KIT/PDGFRA en tumores del estroma gastrointestinal. Fundación Mari Paz Jiménez Casado - FMPJC. 2017-2022.
- Estudio de los determinantes bioloógicos responsables de respuesta prolongada (>5 años) a la inhibición de KIT en tumores del estroma gastrointestinal (GIST). Sociedad Española de Oncología Médica – SEOM (Spanish Society of Medical Oncology). 2018-2022.
- Plataforma Tecnológica de VHIO para estudiar la evolución clonal y la resistencia el tratamiento inmune y tratamientos dirigidos en cáncer. SCITRON. 2017-2022.
- Estudio de los mecanismos de resistencia a la terapia personalizada (inhibidores KIT/PDGFRA) en tumores gastrointestinales de estroma (GIST). Fundación FERO (FERO Foundation). 2020-2022.
- DIVAS-Dissecting VAsculas Sarcomas. Grupo Español de Investigación en Sarcomas – GEIS (Spanish Group of Sarcoma Research). 2020-2022.
- Perfiles de resistencia molecular a la inhibición de KIT/PDGFRA en tumores del estroma gastrointestinal. Asociación Española Contra el Cáncer – AECC (Spanish Association against Cancer). 2020-2024.
- A Multicenter Phase 1, Open-Label Study of DCC-3014 to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Patients with Advanced Tumors. EECC. 2020-2023.
- Start-up - Estudio de los mecanismos de resistencia a la terapia personalizada (inhibidores KIT/PDGFRA) en tumores gastrointestinales de estroma (GIST). Fundación FERO (FERO Foundation). 2021-2022.
Clinical Trials
- INVICTUS: A Phase 3, INterVentional, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of DCC-2618 In Patients with AdvanCed Gastrointestinal Stromal TUmorS who have Received Treatment with Prior Anticancer Therapies. Role: National PI; Advisory Board Member
- CRENOGIST: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Trial of Crenolanib in Subjects with Advanced or Metastatic Gastrointestinal Stromal Tumors with a D842V Mutation in the PDGFRA Gene. Role: National PI
- VOYAGER: An International, Multicenter, Open-label, Randomized, Phase 3 Study of BLU-285 vs Regorafenib in Patients with Locally Advanced Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST). Role: National PI; Advisory Board Member
- INTRIGUE: A Phase 3, Interventional, Randomized, Multicenter, Open-Label Study of DCC-2618 vs Sunitinib in Patients with Advanced Gastrointestinal Stromal Tumors after Treatment with Imatinib. Role: National PI; Advisory Board Member
- SELIGIST: A multicenter, phase Ib/II trial of Selinexor in combination with Imatinib in patients with metastatic and/or unresectable gastrointestinal stromal tumors (GISTs). Role: Global Trial Coordinator
- Study of DCC-3014 in Patients With Advanced Tumors and Tenosynovial Giant Cell Tumor. Role: PI.
Stem Cells & Cancer Group
Héctor G. Palmer
Principal Investigator
Biosketch
Biosketch Héctor G. Palmer
Héctor G. Palmer obtained his PhD in Biochemistry and Molecular Biology from the Universidad Autónoma de Madrid in 2001 for his work at the Instituto de Investigaciones Biomedicas – IIB (CSIC-UAM, Madrid) under the supervision of A. Muñoz. During this time his studies focused on the anti-tumoral capacity of vitamin D analogues on human colon cancer cells.
From 2001 – 2003 he continued to work at the IIB as a Post-Doctoral Fellow exploring the crosstalk between vitamin D receptor and the transcriptional repressor Snail in colon cancer.
In 2003 Héctor was awarded a Marie Curie Intra European Fellowship, and in 2004 he joined the London Research Institute-Cancer Research UK (LRI-CRUK) as a Post-Doctoral Fellow under the leadership of F. M. Watt, during which time he described the vitamin D receptor as a novel transcriptional effector of the Wnt pathway that controls stem cell fate in adult epidermis. He also discovered that the central role of the Wnt signalling in tumor initiation depends on VDR function, opening a new avenue for the use of Vitamin D-based therapies to prevent the development of cancer.
In 2008 Héctor returned to Spain to join the Vall d’Hebron Institute of Oncology (VHIO) as Principal Investigator of the Stem Cells & Cancer Group. His group focuses on the relevance of persistent tumor cells in cancer self-renewal, drug-resistance, relapse, and metastasis.
Summary
VHIO’s Stem Cells & Cancer Group studies the mechanisms that enable tumors to evade effective treatments and progress to advanced stages of disease.
We use multi-omics approaches to reveal unexpected alterations related to tumor and single cell phenotypes. Combining gene editing (CRISPR/Cas) with classical signaling biochemistry in cancer cell lines as well as genetically modified mice, patient-derived organoids (PDO) and xenografts (PDX), our group investigates the functional relevance of these newly identified alterations in patients' response to therapies.
We participate in a global multidisciplinary task force incorporating medical oncologists, surgeons, radiologists, and nurses. This strong collaboration aims to rapidly translate laboratory results to the clinic.
Main research lines include:
Tumor cell dormancy
The study of the intriguing biology of cancer cell dormancy as a driver of chemoresistance, formation of minimal residual disease, and disease relapse in patients.
We previously discovered a core epigenetic network that governs dormancy of tumor cells (Puig et al. 2018)*, and are now investigating the function of TET2, DPPA3 and other epigenetic and transcription factors governing dormancy in greater depth. Importantly, our group is rapidly progressing in developing drugs that modulate dormancy drivers including TET2, and defining novel biomarkers to detect chemo-resistant dormant tumor cells (DTC).
Response to target-directed drugs
We work in close collaboration with oncologists and pharmaceutical companies to identify molecular mechanisms responsible for the sensitivity or resistance to drugs blocking Wnt/beta-catenin, Notch, PI3K/AKT, EGFR/LGR5 or BRAF/MEK/ERK, oncogenic signals (Tenbaum et al. 2012; Puig et al. 2013; Capdevila et al. 2020)**.
Based on our discoveries, we are designing new prescreening tests for the genetic-guided enrolment of patients in clinical trials. Importantly, findings are helping to define new rational drug combinations to treat cancer patients with progressive disease.
Preclinical cancer models
Our group is also expanding and characterizing its PDX collections (CRC, neuroendocrine and peritoneal pseudomyxoma), and optimizing their use in evaluating drug efficacy and metastasis by orthotopic injection and live imaging (TC, PET and Echography).
Lastly, we are developing ambitious projects through the EurOPDX, PERSIST-SEQ, CRCelerate Consortia, co-founded by VHIO. These partnerships comprise all the main reference groups working with PDX, single cell sequencing and cancer models in Europe.
* Puig I, Tenbaum SP, Chicote I, Arqués O, Martínez-Quintanilla J, Cuesta-Borrás E, Ramírez L, Gonzalo P, Soto A, Aguilar S, Eguizabal C, Caratù G, Prat A, Argilés G, Landolfi S, Casanovas O, Serra V, Villanueva A, Arroyo AG, Terracciano L, Nuciforo P, Seoane J, Recio JA, Vivancos A, Dienstmann R, Tabernero J, Palmer HG. TET2 controls chemoresistant slow-cycling cancer cell survival and tumor recurrence. J Clin Invest. 2018 Aug 31;128(9):3887-3905.
**
Tenbaum SP, Ordóñez-Morán P, Puig I, Chicote I, Arqués O, Landolfi S, Fernández Y, Herance JR, Gispert JD, Mendizabal L, Aguilar S, Ramón y Cajal S, Schwartz S Jr, Vivancos A, Espín E, Rojas S, Baselga J, Tabernero J, Muñoz A, Palmer HG. β-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 2012 Jun;18(6):892-901.
Puig I, Chicote I, Tenbaum SP, Arqués O, Herance JR, Gispert JD, Jimenez J, Landolfi S, Caci K, Allende H, Mendizabal L, Moreno D, Charco R, Espín E, Prat A, Elez ME, Argilés G, Vivancos A, Tabernero J, Rojas S, Palmer HG. A personalized preclinical model to evaluate the metastatic potential of patient-derived colon cancer initiating cells. Clin Cancer Res. 2013 Dec 15;19(24):6787-801.
Capdevila J, Arqués O, Hernández Mora JR, Matito J, Caratù G, Mancuso FM, Landolfi S, Barriuso J, Jimenez-Fonseca P, Lopez Lopez C, Garcia-Carbonero R, Hernando J, Matos I, Paolo N, Hernández-Losa J, Esteller M, Martínez-Cardús A, Tabernero J, Vivancos A, Palmer HG. Epigenetic EGFR Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas. Clin Cancer Res. 2020 Feb 15;26(4):902-909.
Strategic goals
- Advance insights into tumor dormancy.
- Study the role of epigenetic factors governing dormancy in chemoresistance, minimal residual disease, relapse, dissemination and metastasis.
- ONIRIA Therapeutics - modulating cell dormancy to combat cancer.
- Develop small drug modulators of cancer cell dormancy to block cancer progression.
- Molecularly-matched targeted therapies.
- Unveil the mechanisms of response to drugs targeting EGFR, BRAF, MEK, ERK, LGR5, Wnt, or PARP.
- Refinement of advanced cancer models.
- Expand our PDX collection and develop new orthotopic models as well as live imaging techniques.
Highlights
- Cancer cell dormancy: We have revealed key epigenetic factors ruling cancer cell dormancy, hypoxia, chemoresistance and tumor recurrence, as well as developed effective small drugs targeting some of these.
- Molecularly-matched cancer therapies: Our group has described relevant determinants of response to BRAF and Notch inhibitors, demonstrated the efficacy of new rational drug combinations, and evaluated minimal residual disease of RET fused tumors.
- Advanced cancer models: In collaboration with several European-funded networks, we have generated and refined new cancer models of colorectal cancer.
Horizons
- ONIRIA Therapeutics spin-off.
We are committed to creating a spin-off company to develop drug modulators of cancer cell dormancy as a novel strategy to combat cancer. We have already developed lead compounds that activate TET2 and show anti-tumoral activity.
For this ambitious project, we have set up a collaboration comprising experts in drug development with experience in similar initiatives. Importantly, given our Institute’s successful track record in launching spin-off companies ONIRIA will be based at VHIO. Our expert team will investigate first-in-class drugs in partnership with VHIO’s clinical investigators who have extensive expertise in early phase clinical studies.
- Revealing new drivers of cancer cell dormancy.
We aim to demonstrate the relevance of different epigenetic or transcription factors as master regulators of dormant tumor cells (DTC) distinctive phenotype. Specifically, we hope to publish our findings on DPPA3 as crucial factor in hypoxia and chemoresistance.
Other drivers governing dormancy are currently under investigation by one of our Post-Doctoral Fellows and two students as part their thesis and Masters degrees, respectively. This research line is technically complex and relatively unexplored. Making a significant contribution to better understanding cancer cell dormancy and chemoresistance thus represents a particular challenge. We aim to identify future drug targets and biomarkers to seek out and eradicate DTC, and reduce chemoresistance and the risk of disease relapse. - Defining new effective therapies based on rational drug combinations.
Based on our discoveries in novel mechanisms of resistance to EGFR, BRAF, MEK, Wnt, Notch, RET, LGR5 or PARP inhibitors, we will design and test novel drug combinations that could benefit patients whose disease has progressed on initial treatments.
This approach, based on the analyses of paired patients’ tumor samples and PDX models treated with matched therapies, is already showing great promise. We expect to report new insights into the mechanisms of action of some targeted drugs that will help guide oncologists to design and assess more precise and effective treatments.
Within the framework of a recently granted EU IMI Innovative Medicines Initiative project, we will perform single cell multiomics analyses to evaluate drug resistance in our PDX models and fresh tissue samples from patients. - Innovating preclinical cancer models.
One of our challenges is to integrate several imaging techniques (TC, PET and echography) for the longitudinal evaluation of mice orthotopically implanted with patient-derived cells, and assess their response to new drug combinations. These comprehensive models could more faithfully recapitulate advanced disease in cancer patients, and therefore constitute a powerful tool in translating our laboratory results to the clinic.
PI paper pick 2021
- Woo XY, Giordano J, Srivastava A, Zhao ZM, Lloyd MW, de Bruijn R, Suh YS, Patidar R, Chen L, Scherer S, Bailey MH, Yang CH, Cortes-Sanchez E, Xi Y, Wang J, Wickramasinghe J, Kossenkov AV, Rebecca VW, Sun H, Mashl RJ, Davies SR, Jeon R, Frech C, Randjelovic J, Rosains J, Galimi F, Bertotti A, Lafferty A, O'Farrell AC, Modave E, Lambrechts D, Ter Brugge P, Serra V, Marangoni E, El Botty R, Kim H, Kim JI, Yang HK, Lee C, Dean DA 2nd, Davis-Dusenbery B, Evrard YA, Doroshow JH, Welm AL, Welm BE, Lewis MT, Fang B, Roth JA, Meric-Bernstam F, Herlyn M, Davies MA, Ding L, Li S, Govindan R, Isella C, Moscow JA, Trusolino L, Byrne AT, Jonkers J, Bult CJ, Medico E, Chuang JH; PDXNET Consortium; EurOPDX Consortium. Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts. Nat Genet. 2021 Jan;53(1):86-99.
- Harmston N, Lim JYS, Arqués O, Palmer HG, Petretto E, Virshup DM, Madan B. Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway. Cancer Res. 2021 Jan 15;81(2):464-475.
FULL LIST OF PUBLICATIONS 2021
- Woo XY, Giordano J, Srivastava A, Zhao ZM, Lloyd MW, de Bruijn R, Suh YS, Patidar R, Chen L, Scherer S, Bailey MH, Yang CH, Cortes-Sanchez E, Xi Y, Wang J, Wickramasinghe J, Kossenkov AV, Rebecca VW, Sun H, Mashl RJ, Davies SR, Jeon R, Frech C, Randjelovic J, Rosains J, Galimi F, Bertotti A, Lafferty A, O'Farrell AC, Modave E, Lambrechts D, Ter Brugge P, Serra V, Marangoni E, El Botty R, Kim H, Kim JI, Yang HK, Lee C, Dean DA 2nd, Davis-Dusenbery B, Evrard YA, Doroshow JH, Welm AL, Welm BE, Lewis MT, Fang B, Roth JA, Meric-Bernstam F, Herlyn M, Davies MA, Ding L, Li S, Govindan R, Isella C, Moscow JA, Trusolino L, Byrne AT, Jonkers J, Bult CJ, Medico E, Chuang JH; PDXNET Consortium; EurOPDX Consortium. Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts. Nat Genet. 2021 Jan;53(1):86-99.
- Harmston N, Lim JYS, Arqués O, Palmer HG, Petretto E, Virshup DM, Madan B. Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway. Cancer Res. 2021 Jan 15;81(2):464-475.
Projects
- PERSIST-SEQ. Building a reproducible single-cell experimental workflow to capture tumour drug persistence. FINANCIAL ENTITY: IMI Program. Pharma Industry and UE (Horizon 2020-JTI-IMI2-2020-20-two-stage). Duration: 2021-2024. PI: Héctor G. Palmer.
- Targeting dormant tumor cells as a new strategy to fight cancer. PI20/00897. FINANCIAL ENTITY: Instituto de Salud Carlos III (ISCIII). Duration. 2021-2023. PI: Héctor G. Palmer.
- First-in-class small drug activators of TET2 for the treatment of cancer FINANCIAL ENTITY: Fundación de la Asociación Española Contra el Cáncer (AECC). Duration: 2020-2021. PI: Héctor G. Palmer.
- Tumor microenvironment-derived factors in localized colon cancer: clinical impact and therapeutic implications. FINANCIAL ENTITY: Fundación de la Asociación Española Contra el Cáncer (AECC). Duration: 2020-2024. PI: Héctor G. Palmer (Coordinator: Andrés Cervantes).
- CaixaImpulse Validate. A novel approach to enhance the therapeutic efficacy of CAR cells. FINANCIAL ENTITY: Fundación Bancaria Caixa d’Estalvis i Pensions de Barcelona. Duration: 2020-2021. PI: Carlos Galdeano.
- Accelerator Award. Pseudomyxoma peritonei: building a European multicentric cohort to accelerate new therapeutic perspectives. FINANCIAL ENTITY: Cancer Research UK (CRUK), Asociación Española contra el Cancer (AECC) & Associazione Italina per la Ricerca sul Cancro (AIRC). Duration: 2019-2024. PI: Héctor G. Palmer. (Consortium Coordinator: Marcello Deraco).
- Accelerator Award. ACRCelerate: Colorectal Cancer Stratified Medicine Network. FINANCIAL ENTITY: Cancer Research UK (CRUK), Asociación Española contra el Cancer (AECC) & Associazione Italina per la Ricerca sul Cancro (AIRC). Duration: 2018-2021. PI: Héctor G. Palmer. (Consortium Coordinator: Owen Sansom).
- EDIReX, EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts. #731105. FINANCIAL ENTITY: EU Horizon2020 Research and Innovation Program. Duration: 2018-2021. PI: Héctor G. Palmer. (Consortium Coordinator: Enzo Medico).
- FINANCIAL ENTITY: Fundación de la Asociación Española Contra el Cáncer (AECC). Duration: 2017-2021. PIs: Isabel Puig and Héctor G. Palmer
Tumor Biomarkers Group
Josep Villanueva
Principal Investigator
Biosketch
Biosketch Josep Villanueva
Josep Villanueva obtained his PhD in Biochemistry and Molecular Biology from the Universitat Autonoma de Barcelona in the year 2000.
In 2002 he accepted a postdoctoral fellowship to join Paul Tempst’s laboratory at the Memorial Sloan-Kettering Cancer Center (MSKCC), New York (USA), where he participated in a new clinical proteomics program aimed at the identification of serum cancer biomarkers. He was appointed as lead scientist in developing a unique automated platform for the measurement of peptides in serum using magnetic beads and a mass spectrometry read-out.
Following the ‘technology phase’, he collaborated with physicians and clinical chemists at MSKCC to demonstrate that a limited subset of serum peptides provides accurate class discrimination between patients with three types of solid tumors and healthy controls. Sequence analysis revealed that these peptides were generated by ‘cancer-type’-specific exopeptidase activities. He then developed and reduced to practice in vitro Exoprotease read-out assays for cancer diagnostic applications.
In 2006 he was promoted as Senior Staff Scientist. Focused on becoming an Independent Investigator, he started developing a longer-term project exploring targeted approaches for tumor biomarker discovery. During this time he developed novel methodology for the high-throughput proteomics profiling of cell-secreted inventories (the ‘secretome’) centered on biomarkers, which led to his first publication as senior author in 2009.
Josep’s postdoctoral work is widely recognized in the proteomics and biomarker discovery field. He first authored all ten clinical proteomic publications published from the Tempst laboratory. Furthermore, the platform that he developed was licensed to a biotech company – this is currently available as a commercial solution for proteomic biomarker discovery.
In 2009, he returned to Barcelona as Principal Investigator of VHIO’s Tumor Biomarkers Group. His research focuses on the discovery of new tumor-specific biomarkers and therapeutic targets using proteomic methodologies to improve cancer diagnostics and therapeutics.
Summary
Tumor cell communication with its microenvironment plays an important role in tumor initiation and progression. Cancer cells hijack the tumor microenvironment ecosystem via paracrine signaling to promote a pro-oncogenic microenvironment that is crucial for the development of primary and metastatic tumors.
We aim to characterize the mechanisms adopted by these cells to communicate amongst themselves as well as with their microenvironment during tumorigenesis, and exploit these data to advance biomarker and drug target discovery.
Our group’s working hypothesis is that cellular signaling pathways undergo alterations during the tumorigenesis process and that these changes are translated into differential protein secretion, which can also potentially be used to identify secreted markers. Furthermore, some of the differentially regulated proteins could be direct extracellular messengers of intracellular signaling pathways contributing to fundamental stages implicated in cancer initiation and disease progression, thus representing potential therapeutic targets.
Our methodological focus centers on profiling the secreted sub-proteome (‘secretome’) of cells by quantitative mass spectrometry. Most secreted proteins contain a signal peptide that directs their sorting to the extracellular space through the endoplasmic reticulum (ER)–Golgi secretory pathway. Strikingly, when secretome profiles are carefully produced and analyzed, they contain hundreds of theoretical intracellular proteins.
Recent reports showing intracellular proteins with alternative extracellular functions suggest that new protein functions associated with alternative subcellular localizations could be implicated in tumorigenesis.
In line with this notion, our recent efforts in the context of therapeutics and tumor invasion have led us to hypothesize that the characterization of non-classical protein secretion could lead to the development of novel anti-cancer therapies.
Strategic goals
- Characterize the role of RAGE in breast cancer invasion and metastasis.
- The characterization of mechanisms adopted by tumor cells to communicate with their microenvironment during treatment to identify secreted response/resistance biomarkers to cancer drug therapies.
- The identification of mechanisms of acquired resistance to current therapies in breast cancer.
Highlights
- We have uncovered a role of RAGE in the cellular plasticity of triple-negative breast cancer (TNBC) invasive cells. We have also shown that cellular plasticity of TNBC cells can be modulated by specific RAGE antagonists. We envisage that these reagents will ultimately serve as new therapeutic tools against this tumor type.
- We have continued to focus on the development of response and resistance biomarkers to cancer drugs used in the clinic to treat TNBC patients. Furthermore, we have been working towards the identification of mechanisms of acquired resistance to current anti-cancer medicines.
Horizons
- We plan to continue studying the role of RAGE in the tumorigenesis of TNBC. Furthermore, we also aim to develop new RAGE antagonists using an in silico approach with the goal of generating novel therapeutic tools against TNBC.
- Our group will continue to focus on identifying new strategies to overcome acquired resistance to cancer drugs that are used to treat TNBC patients in the clinic.
PI paper pick 2021
- Pujals M, Resar L, Villanueva J. HMGA1, Moonlighting Protein Function, and Cellular Real Estate: Location, Location, Location! Biomolecules. 2021 Sep 9;11(9):1334.
Projects
- Diagnostic and Therapeutic implications of the HMGA1-RAGE signaling pathway in Triple Negative Breast Cancer. Funding Agency: Instituto de Salud Carlos III (ISCIII). 2020 – 2022.
- El microambient immune tumoral en la patogènesi i control del linfoma de cèl.lules del mantell. Funding Agency: Fundació La Marató de TV3 2020-2022.
- We are part of CIBERONC’s Programa de Tumores del Tracto Digestivo, as part of the group (Program ID: CB16/12/00259) led by VHIO’s Director and Head of our Gastrointestinal & Endocrine Tumors Group, Josep Tabernero (PI: Teresa Macarulla).
Tumor Immunology & Immunotherapy Group
Alena Gros
Principal Investigator
Biosketch
Biosketch Alena Gros
Over the last 13 years, Alena Gros’ research has focused on understanding and exploiting the naturally occurring T-cell response to treat cancer. Initially trained as a Biologist, she obtained a PhD in Genetics and did a 7- year postdoctoral fellowship working with Steven A. Rosenberg at the Surgery Branch, National Cancer Institute, US.
She has been directly involved in several clinical studies that enrolled patients to receive neoantigen-enriched or 4-1BB+ selected lymphocytes. Her most cited contribution in this field is the identification of PD-1 as a biomarker of tumor-reactive lymphocytes residing in the tumor (JCI 2014), and the use of this marker to develop noninvasive personalized T cell therapies from peripheral blood (Nature Med 2016, JCI 2019). She is an author of 40 peer-reviewed articles and inventor of over 7 patents related to the field of cancer immunotherapy. In 2016, she was awarded with a Miguel Servet I Fellowship and was recruited by VHIO, where she initiated her independent career leading the Tumor Immunology and Immunotherapy Group.
Her group members are international with diverse training backgrounds. Our research focuses on better understanding the immune response to cancer by identifying the tumor antigens recognized by lymphocytes, evaluating the contribution of identified tumor antigens to antitumor responses following treatment with immunotherapy, and studying the interaction between T cells and tumor cells. These research projects will collectively drive novel insights that will enable us to develop more effective T-cell therapies for patients with solid tumors.
Summary
The immune system can recognize and eliminate cancer. However, tumors evade the immune response through multiple mechanisms. Immunotherapies exploit the immune system to attack cancer. Clinical studies have shown that immune checkpoint inhibitors and T-cell-based therapies can mediate tumor regression in patients with metastatic disease. Thus, in addition to surgery, radiation therapy and chemotherapy, immunotherapy has become the fourth pillar of anti-cancer therapy.
Our group’s work has demonstrated that tumor-reactive T cells can frequently be detected circulating in the blood of cancer patients, regardless of the specific tumor type. Tumor-reactive lymphocytes can recognize cancer neoantigens, derived from mutated gene products, and these appear to play an important role in the clinical efficacy of cancer immunotherapies. Furthermore, we have reported biomarkers expressed preferentially on tumor and neoantigen-reactive lymphocytes residing in tumors and in circulation.
Thanks to the support received from the BBVA Foundation's Comprehensive Program of Cancer Immunotherapy & Immunology - CAIMI, as well as other funding agencies, we aim to leverage these biomarkers to reveal T-cell characteristics associated with the clinical efficacy of immune checkpoint blockade in patients treated at the Vall d’Hebron University Hospital (HUVH). In addition, we are currently developing tailored and minimally-invasive T-cell therapies targeting neoantigens derived from peripheral blood.
Through our group’s long-standing collaboration with Elena Garralda, Principal Investigator of VHIO’s Early Clinical Drug Development Group, and Director of our Research Unit for Molecular Therapy of Cancer (UTIM) – CaixaResearch, we recently received authorization from the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS - Spanish Regulatory Agency) in May 2021 to initiate a phase I clinical trial to test the safety and tolerability of neoantigen-selected TILs.
In this clinical trial we use a highly personalized approach (see Figure) to screen for T-cell mediated recognition of mutated antigens using autologous antigen presenting cells that can process and present in all the potential human leukocyte antigen (HLA) restriction elements. In this pilot clinical study funded by the Instituto de Salud Carlos III – ISCIII (Carlos III Health Institute), we aim to treat up to 10 patients with epithelial cancers and melanoma refractory to standard therapies. By enriching for neoantigen-reactive lymphocytes, we hope to extend the efficacy of TIL therapy beyond melanoma.
In summary, our group focuses on better understanding the naturally occurring T-cell response to cancer and establishing ways to exploit these antitumor responses to develop more effective, powerful, and personalized immunotherapies against cancer.
Strategic goals
- Characterize the personalized anti-tumor T-cell response in cancer patients.
- Mine the personalized repertoire of tumor-reactive lymphocytes for potential biomarkers of response to cancer immunotherapy.
- Investigate novel strategies to rapidly identify tumor-reactive lymphocytes as well as the specific target antigens recognized.
- Study the tumor cell intrinsic mechanisms of resistance to T-cell mediated cytotoxicity.
- Develop personalized T-cell-based cancer immunotherapies for patients with solid tumors.
Highlights
- We finalized the clinical grade validations of TIL expansion for the treatment of patients at Vall d’Hebron in collaboration with the Blood and Tissue Bank (BST), a public agency of the Catalan Government’s Department of Health. This work was supported by funding received from the BBVA Foundation and its Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) at VHIO.
- Together with Elena Garralda, Principal Investigator of VHIO’s Early Clinical Drug Development and Director of our Research Unit for Molecular Therapy of Cancer (UITM) – CaixaResearch, we received authorization from the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS - Spanish Regulatory Agency), and initiated patient recruitment for a phase I clinical study to test the safety and tolerability of neoantigen-selected TIL for patients with solid tumors refractory to standard therapies.
- Our group is now collaborating with Holger Heyn, Team Leader at the National Center for Genomic Analysis (CNAG-CRG), Barcelona, to study the T cells infiltrating endometrial cancers with unprecedented detail, at the single cell level. These studies will guide the identification of T cells with superior traits for adoptive cell transfer.
Horizons
- Track tumor-specific T cell responses and their dynamics following treatment with immune checkpoint inhibitors using single-cell multi-omics.
- Use immunopeptidomics to prioritize hot-spot driver cancer neoantigens naturally processed and presented on HLA and identify TCRs targeting them to develop personalized gene-engineered T-cell therapies.
- Develop minimally-invasive personalized T-cell based therapies for patients with solid tumors.
PI paper pick 2021
- Gartner JJ, Parkhurst MR, Gros A, Tran E, Jafferji MS, Copeland A, Hanada KI, Zacharakis N, Lalani A, Krishna S, Sachs A, Prickett TD, Li YF, Florentin M, Kivitz S, Chatmon SC, Rosenberg SA, Robbins PF. A machine learning model for ranking candidate HLA class I neoantigens based on known neoepitopes from multiple human tumor types. Nat Cancer. 2021 May;2(5):563-574.
- Arenas EJ, Martínez-Sabadell A, Rius Ruiz I, Román Alonso M, Escorihuela M, Luque A, Fajardo CA, Gros A, Klein C, Arribas J. Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation. Nat Commun. 2021 Feb 23;12(1):1237.
- Kast F, Klein C, Umaña P, Gros A, Gasser S. Advances in identification and selection of personalized neoantigen/T-cell pairs for autologous adoptive T cell therapies. Oncoimmunology. 2021 Jan 7;10(1):1869389.
Projects
- Grantor: Miguel Servet (Type 2). Title: Characterization of neoantigen-specific T cells and identification of predictive biomarkers of response in patients with MSI and MSI-like CRC treated with anti-PDL1.
- Grantor: Instituto de Salud Carlos III (ISCIII). Title: Terapia celular de próxima generación con TIL específicos de neoantígenos para pacientes con tumores resistentes a inhibidores de puntos de control inmunitario.
- Grantor: Fundación Fero (Beca Fero). Title: Non-invasive personalized T-cell therapies targeting recurrent hot spot driver mutations in cancer.
- Grantor: Fundación BBVA. Alena Gros is a member of the BBVA Foundation’s Immunotherapy & Immunology Program (CAIMI) at VHIO.
- Grantor: La Marató de TV3. Title: Personalized Immunotherapy for Endometrial Cancer.
- Grantor: La Caixa Health Research. Title: Development of enabling technologies for T-cell immunotherapy of solid tumors.
- Grantor: Ministerio de Ciencia e Innovación. Title: Mining the molecular determinants of the personalized T-cell response in cancer patients to develop more effective immunotherapies.