This year’s Vall d’Hebron Institute of Oncology’s (VHIO) Scientific Report branding features the infinity symbol. Indeed, flipped on its head it is of course a number 8 in celebration of VHIO embarking on its second decade ahead.
For me, this symbol represents much more than a concept or a figure. Rather, it depicts a virtuous cycle of knowledge; the seamless and unrestricted flow of discovery in oncology from the bench to the bedside and back. It is also illustrative of the multidisciplinary and translational research model for which VHIO is famed.
As I reflect on the past year and consider the current state of oncology within the broader context of precision medicine, the progress we are collectively making to solve cancer sooner is undeniably great.
At the research level, thanks to the past decade’s increased focus on prevention and early diagnosis, as well as the expanding portfolio of potent anti-cancer medicines matched to molecular signatures of individual tumors, we continue to translate progress into proven benefits for our patients.
These successes have been driven, in parallel, through the rapid development of omics platforms and prescreening tests, the better harnessing, sharing and interpretation of big data, and novel treatment approaches.
The recent addition of promising immunotherapeutics to the arsenal of anti-cancer weaponry, coupled with circulating tumor (ct)DNA analysis for more predictive tracking of disease, are helping us to deliver on the true promise of personalized medicine in oncology.
As Director of VHIO, it is both a privilege and pleasure for me to mention just some of the many important contributions driven by our research teams in 2018, often in partnership with colleagues across the globe as well as pioneering international consortia.
These exceptional advances and developments in cancer science and medicine will help us to collectively up the tempo in more effectively reversing cancer resistance and halting metastatic cell spread, in ’real time’, on time.
Let’s dig into a few of the myriad VHIO highlights over this past year:
Cancer modelling, predictive biomarkers and the unmasking of novel drug-targets: three jewels in VHIO’s crown
Empowering predictive and reproducible cancer science
At VHIO, we are dedicated to accelerating robust preclinical data required to reliably guide the clinical development of innovative agents and approaches, as well as evidence its reproducibility before moving into the clinic.
An area of strength is in cancer modelling, with particular emphasis on tuning patient-derived xenograft (PDX), avatar and organoid models to identify factors governing tumor progression and response to therapy. VHIO is both a founding member and sits on the Board of Coordinators to steer strategic directions of the EurOPDX Consortium–Translating Knowledge in Oncology (launched in 2013).
Announced in 2018, the EurOPDX partners secured funding from the EU’s Horizon 2020 research and innovation programme to construct a repository for the open access sharing of more than 1500 established PDX models, complete with their clinical, molecular and pharmacological annotations: EDIReX–EurOPDX Distributed Infrastructure for Research on patient-derived cancer Xenografts.
Coordinated by Enzo Medico, Candiolo Cancer Center IRCCS (Turin, Italy), this platform counts on the research excellence of 19 entities spanning 13 European countries, including VHIO.
With one of the biggest PDX collections in Europe, particularly in breast, glioblastoma and colorectal cancers, we will assume a leading role in strengthening this essential open access resource. In addition, as we strive to more accurately model immunotherapy strategies through our generation and development of humanized PDX to validate the performance of T-cell bispecific antibodies, our research promises to reveal precious insights that we will be sharing via this exciting new platform (see sub-section, Immunotherapy: hope v’s the over-hyped, in this Foreword).
A second pan-European undertaking fueled by EU’s Horizon 2020, MESI-STRAT will establish the interplay of breast cancer metabolism and oncogenic signaling by systems medicine approaches. Co-coordinated by Kathrin Thedieck, University Medical Center Groningen (The Netherlands), and Tobias Anzeneder, PATH Biobank (Munich, Germany), this consortium combines the expertise of 14 partners including VHIO. It centers on breast cancer metabolism as a novel approach for the stratification of patients, tracing resistance, and better informing clinical decision-making throughout the course of endocrine therapy.
VHIO’s library of in vitro and in vivo models will provide data required to individualize and validate MESI-STRAT’s computational models. Violeta Serra, PI of our Experimental Therapeutics Group, will help to develop metabolite marker panels to guide established targeted therapies for the treatment ER-positive tumors that are resistant to endocrine therapy.
Coordinated by Cristina Saura, PI of VHIO’s Breast Cancer & Melanoma Group, we will also interrogate the predictive value of specific biomarkers in liquid biopsies from patients enrolled in our clinical studies with novel therapies.
Busted: exposing new drug-targets
A study (1) published in The Journal of Clinical Investigation, led by PI of our Stem Cells & Cancer Group, Héctor G. Palmer, in collaboration with several other VHIO groups, revealed a novel drug-target to ‘strangle’ sleeper cancer cells.
Their findings have evidenced an epigenetic enzyme, TET2, as a biomarker to identify dormant tumor cells (DTC), also known as slow-cycling cancer cells (SCCC), which go undetected by current treatments that have mostly been designed to target rapidly dividing tumor cells.
Having secretly travelled and settled in other parts of the body, when DTC awake they behave like cancer stem cells, regenerate the original tumor and drive metastasis in patients thought to be cured.
Palmer and colleagues identified TET2 as the Achilles heel of dormant tumor cells and also sought to develop novel inhibitors aimed at preventing their seeding of metastasis. By establishing that TET activity correlates with elevated levels of 5hmC as well as a greater risk of resistance to therapies and disease relapse, these insights into the molecular intricacies of DTC provide a promising translational opportunity toward potentiating treatments, preventing cancer recurrence, and extending the survival of patients.
Teaching an old protein new tricks, research headed by Josep Villanueva, PI of our Tumor Biomarkers Group, in collaboration with the CIBERONC Center for the Biomedical Research Network in Oncology (scientifically led by VHIO’s Joaquín Arribas, Co-Director of our Preclinical and Translational Research Program), has unmasked extracellular HMGA1 as a novel drug target for the treatment of metastatic triple-negative breast cancer (TBNC) and a predictive biomarker of cancer cell spread.
By elegantly reporting the correlation between HMGA1 secretion and its nucleus-to-cytoplasm migration in Clinical Cancer Research (2), these important insights change the view on this protein’s role in tumorgenesis, and support the relevance of unconventional protein secretion in cancer diagnostics and therapeutics.
Led by our Mouse Models of Cancer Therapies Group, directed by PI Laura Soucek, a study published in Oncotarget (3) offers preclinical evidence for the role of a novel BET inhibitor in more effectively treating Kras-driven cancers.
Their results in mouse models of Kras-mutated pancreatic ductal andenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) support the further evaluation of BET inhibition in solid tumors in the clinic. Future directions will need to focus on how to potentiate the blocking of BET either as monotherapy or in combination with other drugs, as well as reduce the toxicity reported in some early clinical studies.
Another VHIO contribution to the science of cancer progression this year was reported in Nature Communications (4) by Sandra Peiró and her Chromatin Dynamics in Cancer Group. They showed that the inner nuclear protein, lamin B1, is necessary for the 3D genome rewiring required to transform an epithelial cell and enable it to migrate and invade other tissues.
By reducing levels of this protein, her team showed that by effectively eliminating part of it, the cells lose their ability to become mesenchymal stem cells, thus reducing their capacity to travel and relocate. These findings represent another forward step towards better understanding the drivers of disease spread.
Powerful blows against BRCA1/2 mutated disease
Speaking of drug-targeting, in our determined pursuit to establish more effective treatment strategies that target vulnerabilities in BRCA1/2-associated cancer, my first selection are the results from the phase III SOLO-1 multi-center trial led by Kathleen Moore, Stephenson Cancer Center (Oklahoma, USA), and co-authored by Ana Oaknin who leads our Gynecological Malignancies Group.
Selected to first outing at the 2018 ESMO Congress (19-23 October, Munich, Germany), during the Presidential Symposium that I co-chaired and timed in parallel to publish in The New England Journal of Medicine (5), data showed that treatment with olaparib maintenance therapy led to a spectacular extension of progression-free survival by 3 years in over 50% of patients with newly diagnosed advanced ovarian cancer. This pivotal study also revealed that this novel treatment approach reduced the risk of disease progression by an impressive 70%.
Judith Balmaña’s Hereditary Cancer Genetics Group, in collaboration with our Breast Cancer & Melanoma (PI Cristina Saura), and Experimental Therapeutics (PI Violeta Serra,) Groups co-authored a paper in The Journal of Clinical Oncology (6) from a USA-Spanish multicenter phase II trial that signposts new direction in the treatment of BRCA1/2 mutated advanced breast cancer.
Blocking transcription and induces DNA double-strand breaks leading to apoptosis, they have proposed the novel agent lurbinectedin as a potentially more powerful therapy against this tumor type. Importantly, this research also included a translational sub-study assessing potential mechanisms of resistance to this promising inhibitor. These important findings were covered in a news review published by The Lancet Oncology (7).
At the preclinical and translational level, research led by Violeta Serra, in collaboration with the other VHIO groups mentioned in my previous highlight, among others, culminated in two publications (8) (9), this year that provided important new insights into resistance and response to PARPi both in BRCA-mutated breast cancer and beyond.
This year the group developed their RAD51 foci assay, PARPiPRED, which accurately identifies germline BRCA tumors that have restored functionality, as well as other tumor types that are sensitive to these inhibitors. Importantly, they have also shown that this test is both feasible in routine tumor samples and a simple technique to apply.
While we hope for ease and speed in its translation to the clinic, further studies are now underway to more precisely define the sensitivity and specificity of PARPiPRED in predicting PARPi benefit and thus more informed patient selection.
Immunotherapy: hope vs the over-hyped
The promise and performance of novel immunotherapies (not to mention the price tags of those approved to-date) have once again been under intense scrutiny this year, with several editorials and opinion pieces, including one by The Lancet Oncology (10), calling for an adjusted alignment of expectations with current realities.
I also touched on this in an editorial that I was invited to pen for ESMO Open (11) to mark the mid-term of my Presidency of the European Society for Medical Oncology.
The emergence of these novel drug contenders should be celebrated, but much work still needs to be done to better predict those patients who would most likely benefit from them, extend their early promise to more patients as well as tumor types–either as monotherapy or, most likely, in combination, and tackle important concerns regarding safety and toxicity.
While immunotherapies are largely not yet benefiting as many patients as they promise, I believe that we are on the cusp of change. I am not alone: at the close of the year, several reports in the specialized and general media including Forbes (12) magazine as well as the official blog of the American Association for Cancer Research (AACR), CANCER RESEARCH Catalyst (13), predicted great things to come in 2019.
This will only happen by extending our efforts aimed at potentiating and personalizing this armory to successfully unleash the power of the immune system in a greater number of individu als to attack disease. We must deliver the robust immune data required to better guide treatment decisions that benefit all patients and not just the so-called ‘super-responders’.
VHIO continues to lead cancer discovery in this direction. Our preclinical research culminated in a publication in Science Translational Medicine (14), showing that a decade-old protein, p95HER2, previously described by VHIO, offers a target for novel therapy that steers the immune system to hone in on and eliminate tumor cells.
Findings reported by our Growth Factors Group, led by Co-Director of Preclinical & Translational Research at VHIO and ICREA Professor, Joaquín Arribas, revealed that p95HER2-T cell bispecific antibody (TCB), enables a targeted response by attacking cancer cells directly without affecting normal ones.
Thanks to the distinct specificity of TCB and this particular protein’s exclusive location in malignant cells, the authors have described a ‘home-delivery’ of immune-based therapy. Approximately 10% of patients with HER2-positive breast cancers expressing p95HER2 could ultimately stand to benefit from this novel strategy.
Having now completed the preclinical phase of development, Joaquín’s team is now focusing on advancing this therapy so that it can be administered in patients enrolled in clinical trials. Next steps will also include developing additional therapies against p95HER2 such as antibody-drug conjugates or chimeric antigen receptors (CARs).
I am excited to report our Experimental Hematology Group, directed by Francesc Bosch is participating in the first international, multi-center phase II clinical trial, TRANSCEND World, to assess the efficacy of chimeric antigen receptor (CAR) T cell therapy for patients with aggressive B-cell non-Hodgkin lymphoma. We are the first Spanish site to conduct a CAR T cell clinical study in this population and also the first to have been granted authorization for patient enrolment.
In collaboration with an additional 15 selected sites across Europe as well as two in Japan, this study has been designed to determine the efficacy and safety of JCAR017 to treat clinically selected adult patients with relapsed or refractory disease. The investigators will seek to validate the promising response rates and superior profile of this immunotherapy observed in early phase trials.
A paper (15) in The New England Journal of Medicine, co-first authored by Enriqueta Felip who leads our Thoracic Tumors & Head and Neck Cancer Group, showed promise for the more effective treatment of patients with metastatic non-small-cell lung cancer (NSCLC). Results from a phase II study reported that treatment with pembrolizumab paired with chemotherapy led to higher rates of response as well as longer progression-free survival than with chemotherapy alone.
This study exemplifies the progress that we are making by empowering immunotherapeutics in combination with the cornerstones of cancer therapy–chemotherapy, surgery and radiation. We are also better understanding the cellular and molecular mechanisms modulating immune response and learning from the outcomes of immune-based clinical trials.
Flanking our other research programs and priorities, the Obra Social ”la Caixa” International Program for Cancer Research and Education, as well as the BBVA Foundation’s Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI), represent pioneering research endeavors aimed at delivering on the true promise of this array of novel ‘immunoarmory’ in oncology.
Guiding treatment decision making through novel approaches, platforms and scales
Liquid biopsies: ready for prime time?
At the preclinical and translational level, VHIO was the first academic test center to incorporate in-house BEAMING liquid biopsy RAS biomarker technology (2015). We have since made significant progress in validating and developing liquid biopsy technologies for the more effective, less invasive monitoring of cancer in real time.
These efforts, focused on both ctDNA and tumor educated platelets (TEP), continue to advance thanks to our multidisciplinary teams in collaboration with our two of VHIO’s core facilities, our Cancer Genomics and Molecular Oncology Groups headed by Ana Vivancos and Paolo Nuciforo, respectively.
This year, Joan Seoane, Co-Director of our Preclinical and Translational Program, also an ICREA Professor, was the corresponding author of a paper published in Clinical Cancer Research (16), showing proof-of-concept that cerebrospinal fluid (CSF) can be exploited for liquid biopsies as it contains ctDNA.
Carried out in collaboration with other researchers and clinical investigators at VHIO, as well as oncologists, pathologists and neurosurgeons across the Vall d’Hebron Barcelona Hospital Campus, this study has not only unmasked the molecular characteristics of diffuse gliomas but also promises a more precise and rapid diagnosis that could help steer treatment decision making matched to the classification of these tumors, as well as more closely monitor the course of disease and response to therapy.
Ready for prime time? Not quite. My caution is echoed in a superb commentary in Annals of Oncology (17), authored by Ana Vivancos, with co-contributors, Elena Élez, Clinical Investigator and Molecular Oncologist of our Gastrointestinal & Endocrine Tumors Group led by Teresa Macarulla, and Ramón Salazar, Catalan Institute of Oncology – ICO.
Reviewing a study (18) in Annals of Oncology led by Jakob Vasehus Schou, Department of Oncology, Herlev & Gentofte Hospital, Copenhagen (Denmark), the authors concluded that several issues including timing, simplicity, time to results and cost-effectiveness should all be tackled when considering ctDNA liquid biopsy in the routine testing in cancer patients. They call for clinical trials to bring this exciting technique even closer to the clinic.
Based on the collective body of evidence, coupled with the tremendous progress thus far, I believe this goal is well within reach.
Facilitating the in-depth, accelerated interpretation of cancer genomes
At the core of VHIO’s research activities lies our suite of cutting-edge core technology platforms, which provide our teams with the necessary expertise to apply next-generation whole-genome sequencing for precision oncology as well as develop and improve existing applications to drive faster results.
Our prescreening program, powered by VHIO’s Cancer Genomics and Molecular Oncology Groups, led by Ana Vivancos and Paolo Nuciforo respectively, performs molecular profiling in more than 1500 patients per year as candidates for enrolment in early phase clinical trials carried out at our Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa”, directed by Elena Garralda.
Two of VHIO’s guiding principles are team science and the open exchange and sharing of data to accelerate precious insights in oncology. This has resulted in numerous cross-border alliances and partnerships; several in the form of international consortia, others in novel platforms, programs as well as value framework tools.
Our Oncology Data Science (ODysSey) Group directed by Rodrigo Dienstmann, is dedicated to interpreting and exchanging meaningful mass data in oncology.
As a reference in driving ‘big’ data-derived insights and exploring molecular profiles to more precisely guide treatment decisions, VHIO was invited to participate the American Association for Cancer Research’s (AACR) Project GENIE: Genomics Evidence Neoplasia Information Exchange.
I am proud to report that VHIO is the only GENIE member from Spain, selected for our expertise in better identifying and describing the clinical relevance of driver genomic alterations that trigger cancer.
Rodrigo has pioneered the design of several open access online tools to help physicians and investigators interpret genomic data and apply this knowledge in practice. Published this year in Genome Medicine (19), Rodrigo and VHIO’s Ana Vivancos co-authored a paper describing the Cancer Genome Interpreter (CGI) platform.
Led by ICREA Professor Nuria Lopez-Bigas, Institute for Research in Biomedicine (IRB, Barcelona), CGI represents an important step in providing the scientific community with access to this data in a more structured, consolidated and user-friendly way.
Speaking of cancer classification, 2018 celebrated the launch of the European Commission Horizon 2020-supported project led by Annette Byrne, Royal College of Surgeons in Ireland (Dublin), powered by 14 partners, including VHIO: COLOSSUS–Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions.
Set to simplify and standardize choices for the selection of targeted cancer therapies, the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) published in Annals of Oncology (20).
Led by Joaquin Mateo, Principal Investigator of our Prostate Cancer Translational Research Group, also co-authored by Rodrigo Dienstmann, this new tumor DNA scale classes alterations according to their relevance as markers for the selection of patients matched to targeted treatments, based on the strength of clinical evidence.
Importantly, this new grading system will help guide physicians to distinguish between the genetic alterations that are important for treatment decisions or access to clinical trials, and those which are not.
The Last Word
While the important advances described so far (and more to follow) are gratifying, there is much more work to be done.
Due to late-stage diagnosis, metastatic cell spread, drug resistance and disease relapse, treatment options for an unacceptable number of patients are anything but limitless. They are finite, as seen in the daunting global cancer data.
Recently published statistics in the GLOBOCAN 2018 database (21) report that the cancer burden rose to 18.1 million new cases and 9.6 million cancer deaths in 2018. Additionally, cancer cases are forecast to rise by 75% over the next two decades.
While we can be optimistic that personalized medicine in oncology is starting to happen in practice, we still have far to travel if we are to extend our successes in cancer research to an increasing number of our patients.
VHIO’s talents can only continue to do so thanks to the precious funding received from our treasured institutional supporters–the Generalitat de Catalunya, Fundació Privada CELLEX, FERO Fundación de Investigación Oncológica, Fundació Bancària ”la Caixa”, Fundación BBVA,, as well as our many other supporters, funding entities and agencies.
Year in, year out, VHIO’s preclinical, translational and clinical teams work tirelessly to broaden the array of more effective treatments and enabling technologies tailored to the specificities of individual patients. Importantly, we also do so in collaboration.
I believe in forging essential collaborations with other specialties and partners. We can only continue to tackle the current challenges that are impacting on our ability to more rapidly advance precision medicine against cancer together.
I am confident that we can collectively turn obstacles into opportunity and optimal outcomes for all stakeholders in oncology. Above all, we must continue to listen and respond to the needs of those who matter most–our patients.
As VHIO embarks on its second decade ahead, I am confident that we can, and will, do even better.
Director, Vall d’Hebron Institute of Oncology (VHIO)
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