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.
Our group focuses on the interplay between stress responses, cellular plasticity and cancer. Cellular plasticity is recognized today as a critical feature of cancer cells that enable them to transit between different cellular states and promote tumor growth, disease progression after therapy, and metastasis.
We have 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 observations 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 metastasis.
Our main objective is to better understand 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 findings 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 four years we 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.
The identification of tumor-microproteins could be crucial in 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 2020, we have expanded our microproteins studies. Using a peptidomics approach, the group has 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.
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:
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 (published in Mol. Cell, FEBS J., and Oncogene). We have also discovered an important role for lamin B1 in the reorganization of 3D chromatin structure during EMT (published 2018, Nat. Commun.).
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.
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.
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.
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 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 HRR functionality and develop resistance to PARPi. We have developed an assay, the RAD51predict test, which accurately identifies germline BRCA tumors that have restored HRR functionality and become resistant to these drugs. Importantly, this test also identifies tumors that are sensitive to PARPi through HRR alterations 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. HRR-deficient tumors have been shown to 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 HRR-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 through collaborations with other groups including VHIO’s Molecular Oncology, and Oncology Data Science – OdysSey Groups directed by Paolo Nuciforo and Rodrigo Dienstmann, respectively.
Our team has significantly advanced the understanding of 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.
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.
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 towards improving outcomes for these patients is therefore critical.
Evolving heterogeneity is among one of the major challenges that are currently hampering our efforts aimed at more effectively treating brain cancers. We focus on inter-tumor heterogeneity and evolution that includes genomic heterogeneity, cancer initiating cells and stroma/immune cell heterogeneity – including the study of TGF-β and LIF.
Tumors are composed of a mosaic of cell subclones that differ in their genomic alterations. We explore genomic diversity present in glioblastoma and analyze intratumor genomic heterogeneity as it evolves over time in response to therapy. Our group is designing tools to monitor evolving genomic heterogeneity and study the use of liquid biopsies for brain cancer through the study of circulating cell free tumor DNA in cerebrospinal fluid from patients.
Specifically, we are driving cerebrospinal fluid as liquid biopsy for the real time policing of brain cancer closer to the clinic. Reflective of our expertise in developing this novel approach in medulloblastoma and central nervous system lymphoma, we have authored several research articles (i.e. Escudero et al. Nature Comm. 2020; Bovillo et al. Haematologica 2020).
While no biomarker derived from liquid biopsy against these tumor types has yet been validated and integrated into clinical practice, there is an increasing body of evidence in the literature, including our findings, that points to its efficacy in the real time evaluation of malignant disease and potential to better inform and guide the therapeutic management of patients.
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. Increasing 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 regard, we have reported that the cytokine LIF assumes an essential role in the tumor microenvironment and is consequently a promising therapeutic target.
We have now shown that the novel agent MSC-1, developed by VHIO, inhibits LIF and has a dual mechanism of action. In tumors expressing high levels of LIF, this protein promotes the proliferation of cancer stem cells. LIF blockade eliminates these tumor-initiating stem cells, putting the brakes on metastatic cell spread and disease recurrence.
Additionally, elevated LIF expression disables the anti- tumor alarm system and stops the immune system from thwarting cancer’s plans. Blocking LIF consequently reactivates the alarm to call an anti-tumoral immune response.
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.
This year, 2020, has been a very unusual year for the scientific community due to the outbreak of COVID-19. Despite the restrictions imposed by the pandemic, I am proud to report that our group has managed to continue working on all our projects at an excellent pace.
We continued to pursue our research on mechanisms of resistance to targeted therapies and most importantly, how to overcome it by showing that breast cancers resistant to T-DM1, an antibody-drug conjugate ADC)- can be efficiently treated with the second generation ADC SYD985 (Nadal-Serrano et al.).
Our group has also contributed to determining the clinical value of plasma cell-free DNA and the efficacy of PI3K inhibition in gastrointestinal tumors and (Serrano et al; García-Valverde et al.). Finally, we have collaborated in a position paper on how to enhance global access to cancer medicines (Cortes el al.)
In addition, our ever-expanding platform of breast and pancreatic cancer patient-derived experimental models has enabled us to establish several fruitful collaborations with other groups at VHIO. We have collaborated in the characterization of the genetic abnormalities that determine sensitivity to Akt inhibitors (Gris-Oliver et al.), and in defining how epigenetic changes regulate the accessibility of chromatin in triple negative breast cancer (Cebrià-Costa el al.).
Regarding extramural collaborations, other groups have used our platform to identify precision therapies against co-occurrence of driver alterations (Mateo et al.) and novel therapies (Ferronato et al.).
In parallel, we have continued our research into novel immune therapies by generating novel CARs (chimeric antigen receptors). With the knowledge accumulated during the development and characterization of bispecific antibodies, we have been able to efficiently develop our CARS that are directed against the p95HER2 protein; only present in some mammary and gastric tumors, and completely absent in normal tissues. Importantly, this project has been funded by the Spanish Association against Cancer (AECC) for the next five years.
Mention must also be made regarding the continued backing and support received from the Breast Cancer Research Foundation (BCRF), for which we are extremely grateful.
Lastly, in 2020, our Principal Investigator, Joaquín Arribas, stepped down as Scientific Director of the Centro de Investigación Biomédica en Red (CIBER- ONC: Center for the Biomedical Research Network in Oncology), to join the Hospital del Mar Medical Research Institute (IMIM), as Director.
Joaquín will continue to serve as Principal Investigator at VHIO to both lead and participate in our aforementioned research lines and projects with other groups.
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 Mouse 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, and a Reviewer for Anti-cancer Drugs, BBA (Biochimica et Biophysica Acta), BioDrugs, BioEssays, Cancer Discovery, Cancer Immunology and Immunotherapy, Cancer Immunology Research, Cancer Research, Cancer Treatment Review, Cell Chemical Biology, Clinical Cancer Research, Current Pharmaceutical Design, Developmental Dynamics, Drug Discovery Today, E-Biomedicine, eLIFE, Gastroenterology Research and Practice, 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, Nature, Nature Cell Biology, Nature Communications, Nature Medicine, Oncogene, Oncogenesis, “Oncology” books iConcept Press Ltd, Oncotarget, Peptide Science, Plos One, Science Translational Medicine, Therapeutic Advances in Chronic Disease, 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 in her group – VHIO and ICREA, she co-founded the spin-off company Peptomyc S.L. In 2015, she was also appointed Associate Professor at the Universitat Autònoma de Barcelona (UAB).
Laura serves on the Ethical Committee for the Use of Experimental Animals (CEEA), the main body responsible for the ethical use of laboratory animals in Catalunya.
She is also a member of the directive Scientific Committee of VHIO as well as the FERO Foundation.
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).
Our group has continued to contribute to cancer research in general and, more specifically, as a leader in the Myc field by (co) authoring a number of reviews. One explores new therapeutic options targeting Myc proteins in lung cancer. Two others focused on Omomyc – our Myc inhibitor – and described the two decades of work that has gone into developing this mini-protein therapeutic and demonstrating that Myc can be targeted clinically. The second one delved into the structural and biophysical properties of Myc, which are key to the development of specific and effective anti-Myc drugs.
An additional review, co-authored by leading Spanish researchers in oncology including Laura, discussed new paradigms and disruptive ideas currently under development in Spain.
This year has also celebrated several collaborative successes:
Our work with Gerard Evan’s laboratory has led to the demonstration that Myc instructs and maintains the pancreatic adenocarcinoma phenotype. This important paper published in Cancer Discovery, advances insights into the role of Myc and its connection to Ras-induced tumors.
Finally, we contributed to a manuscript headed by Jordi Alcaraz and published in Cancer Research, showing that epigenetic SMAD3 repression in tumor-associated fibroblasts reduces fibrosis and sensitivity to the antifibrotic drug nintedanib in lung squamous cell carcinoma
Joaquin Mateo joined the Vall d’Hebron Institute of Oncology at the end of 2017 from the Institute of Cancer Research – Royal Marsden NHS Foundation Trust (London, UK), where he pursued his career under the mentorship of Johann de Bono.
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).
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 Recommentations 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.
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, 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), Fundacion FERO, and the European Commission’s H2020 research program. In 2020, he obtained one of the prestigious AECC LAB Awards for emerging groups.
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.
Over the last decade, we have witnessed a revolution in the treatment of metastatic castration-resistant prostate cancer (mCRPC) which is an advanced and lethal form of prostate cancer. A deeper understanding of its underlying biology has led to the development of compounds targeting the androgen signaling pathway and the immune system, as well as taxanes and radiopharmaceuticals.
Despite these advances in more effectively managing mCRPC, it remains a lethal disease resulting in significant morbidity and mortality globally. Arguably, the most critical need in drug development against CRPC is treatment molecular stratification. In parallel efforts must continue to center on identification of robust predictive biomarkers of response and the development of targeted anti-cancer therapies. The advent of these novel treatments has driven tumor evolution towards a shift in the genomic landscape observed in patients with advanced disease. We embrace a comprehensive and integrative approach to research. As such, our group encompasses molecular biology, tumor genomics, clinical trials and computational sciences in order to develop precision medicine strategies to treat advanced prostate cancer based on predictive biomarkers of response. Defects in DNA damage repair genes (DDR) -particularly in double- strand breaks- are present in 20-25% of mCRPC cases, and allow us to study how we can deliver more precise cancer treatment and care. Some of these mutations have prognostic and predictive implications which are crucial in delivering on the promise of personalized medicine in oncology.
This year, we reported on final results for the registration trial of Olaparib, a PARPi,in prostate cancer, leading to its approval in Europe, Canada and the US, among other countries. Still, more work is needed for the optimal delivery of PARPi-based therapies for those patients with DDR gene mutations beyond BRCA2.
Along these lines, our group uses a range of tools (CRISPR gene editing, shRNA, siRNA and pharmacological inhibitors) to generate prostate cancer models and study how tumors adapt their DNA repair machinery; this year we published on optimal combinatory strategies for ATM-deficient cancers. Our interest in cell cycle modulation by DNA damage has also led us to study the senescence-like phenotype observed after exposure to targeted agents, which we hypothesize is a mechanism of drug resistance, and how to target it therapeutically.
Aiming at translating our findings into benefits for patients as rapidly as possible, we study the same genomic and transcriptomic signatures in biopsies from patients with metastatic prostate cancer. In parallel, we collect longitudinal liquid biopsies to study how a tumor evolves during response and progression to targeted agents.
Our research focuses on optimal patient stratification strategies for clinical care, with particular emphasis on combining DNA repair targeting agents with those that inhibit androgen signaling. Importantly, we have launched our first investigator-initiated clinical trials, translating our research studies in the lab to therapeutic interventions in patients.
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.
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: genomically simple sarcomas driven by simple genetic alterations, such as translocations or specific activating mutations; and tumors with complex and unbalanced genomic aberrations. Each of these categories include diverse sarcomas subtypes often with profound differences in their molecular makeup, course of disease and therapeutic approach.
Our group focuses 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 drug resistance.
Ongoing efforts aim at a deeper biological understanding of GIST and other sarcomas in order to advance drug development. One of the major hurdles with a direct impact on patients’ outcomes, concerns the heterogeneity of mechanisms of resistance.
Our overarching goal is therefore to identify crucial molecules and signaling mechanisms in GIST biology that can serve as therapeutic vulnerabilities.
We also continue 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.
Our group is particularly interested in those with pro-survival function to better understand cellular adaptation to driver inhibition, which may eventually be novel therapeutic targets.
We are as interested in performing high- throughput genomic and transcriptomic studies in order to decipher the evolving patterns of resistance in GIST throughout the course of disease, as well as researching liquid biopsy in sarcoma to provide robust evidence that will help to more precisely guide treatment decisions through plasma sequencing.
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.
Our aim is to have a true clinical impact by improving the daily treatment and care of our sarcoma patients. We are proud to report that our Sarcoma Multidisciplinary Unit has been designated as an Expert National Sarcoma Center by the Spanish Ministry of Health, and thus constitutes an optimal setting for translating cancer discovery into clinical benefits.
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 Instituto de Investigaciones Biomedicas in Madrid as a Postdoctoral 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 Postdoctoral 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 cancer stem cells in tumor self-renewal, drug-resistance, relapse, and metastasis.
Héctor G. Palmer’s Stem Cells & Cancer Group studies the mechanisms that enable tumors to evade effective treatments and progress to advanced stages.
His team uses 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 and xenografts (PDX) they study the functional relevance of these newly identified alterations in patients' response to therapies.
Héctor’s group is also part of a global multidisciplinary task force incorporating medical oncologists, surgeons, radiologists, and nurses. This strong collaboration means that laboratory results can be rapidly translated to the clinic.
Main research lines include:
Tumor cell dormancy
The study of the intriguing biology of cancer cell dormancy that is responsible for chemoresistance, formation of minimal residual disease, and disease relapse in patients.
His team discovered a core epigenetic network governing dormancy of tumor cells (J Clin Invest. 2018), and is now investigating the function of TET2, DPPA3 and other epigenetic and transcription factors governing dormancy in greater depth. Importantly, they are 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
This group works 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 (Nat Med. 2012; Clin Can Res. 2014; Clin Can Res. 2019).
Based on their discoveries, they are designing new prescreening tests for the genetic-guided enrolment of patients in clinical trials. Crucially, findings are helping to define new rational drug combinations to treat cancer patients with progressive disease.
Advanced pre-clinical models of cancer
The group is also expanding and characterizing its PDX collections (CRC, neuroendocrine and peritoneal pseudomyxoma), and improving their potential to evaluate drug efficacy and metastasis by orthotopic injection and live imaging (TC, PET and Echography).
Lastly, the investigators are developing ambitious projects through the EuroPDX Consortium, a collaboration that VHIO co-founded which incorporates all the main reference groups working with PDX in Europe.
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.
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.
Our main aim is to characterize the mechanisms adopted by these cells to communicate amongst themselves as well as with their microenvironment during tumorigenesis. We aim to exploit these data to advance biomarker and drug target discovery.
Our team’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 progression, therefore representing potential therapeutic targets.
The methodological focus of our group 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. One of the most striking observations when secretome profiles are carefully produced and analyzed is that 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 implicated in tumorigenesis.
In line with this notion, our recent efforts within 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.
Alena received her PhD from the Universitat de Barcelona, Spain. During her graduate training she worked with R. Alemany at the Catalan Institute of Oncology (ICO), where she investigated novel strategies to potentiate the antitumor efficacy of oncolytic adenovirus through the enhancement of viral release.
She then joined S. Rosenberg’s group at the National Institutes of Health, NCI (USA), where she remained for 7 years. Her work at the NCI led to the identification of biomarkers that can guide the detection and isolation of tumor-reactive and mutation-specific T cells from the tumor and peripheral blood of cancer patients. These findings have important implications for making T-cell based immunotherapies more widely available. In 2016, Alena received a Miguel Servet grant and joined VHIO to start her independent career as Head of the Tumor Immunology and Immunotherapy Group.
Our team members are international with diverse training backgrounds. Our research centers on better understanding the immune response to cancer by identifying the tumor antigens recognized by lymphocytes, evaluating the contribution of the tumor antigens identified to antitumor responses following treatment with immunotherapy, and studying the interaction between the T cells and the 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.
The immune system can recognize, hone in on and eliminate cancer. Through multiple mechanisms however, tumors can evade the immune response.
Immunotherapies against cancer exploit the immune system to more effectively attack disease. Clinical studies have shown that immune checkpoint inhibitors and T-cell-based therapies can mediate tumor regression in cancer patients with metastatic disease. Thus, in addition to surgery, radiation therapy and chemotherapy, immunotherapy is increasingly representing the fourth pillar of anti-cancer therapy across various tumor types.
Despite encouraging antitumor responses, currently only a fraction of patients treated with immune-based therapies respond, and some unfortunately report autoimmune- related adverse events. There is therefore a critical need to develop and personalize these promising treatments.
To do so, and thanks to the support received from the BBVA Foundation's Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) at VHIO, we study mechanisms of response, toxicity and resistance to cancer immunotherapeutics in patients at the Vall d’Hebron University Hospital (HUVH). We aim to identify biomarkers of response in liquid biopsies.
One correlative biomarker described to-date is mutation burden. Tumor-specific somatic mutations are optimal targets for cancer immunotherapy and render tumors immunogenic; some of these can bind to the patients’ human leukocyte antigen (HLA) molecules and elicit T-cell responses.
We adopt a highly personalized approach to screen for T-cell mediated recognition of mutated antigens as well as shared antigens using autologous antigen presenting cells that can process and present in all the potential HLA restriction elements.
Following this strategy, we aim to establish whether the presence of lymphocytes recognizing these antigens is associated with response. In parallel, we plan to advance personalized T-cell therapies to treat metastatic colorectal cancer, which is largely resistant to current anti-cancer strategies. We have recently filed an investigational new drug (IND) application to the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS - Spanish Regulatory Agency), in February 2021 that will enable us to treat patients with metastatic epithelial or immunotherapy refractory cancers with neoantigen-reactive TILs using this personalized approach. By enriching for neoantigen-reactive lymphocytes, we hope to enhance the efficacy of TIL therapy in epithelial cancers.
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.