2014 Scientific Report

VHIO in 2014: the transformative
power of forward-thinking talent

(please browse subchapters below)

Foreword/

As I reflect on the past year, not only considering the many positive advances reported by VHIO's outstanding and committed multidisciplinary teams but also major achievements of our colleagues from comprehensive cancer centers of excellence around the globe, I am pleased to report that yes, we are collectively progressing in rendering precision medicine in oncology a reality for an increasing number of patients.

There are many factors that have led us to this turning point in the delivery of more precise and powerful anti-cancer therapies. Important advancements in defining the molecular basis of cancer, for example, have enabled us to leverage those insights in the selection of rational, targeted therapies.

We can most certainly afford to be optimistic, but, with caution. I was recently asked to respond to the question: Will all cancer patients be treated by targeted therapies in the next ten years? On the one hand, while translational research efforts are driving cancer discovery at a rapid pace, cuttingedge technologies are becoming yet more powerful and indeed precise, and the lower costs associated with genomic sequencing and pre-screening platforms are making precision medicine more accessible to more of our patients. But we still have a long road to travel. Regretfully, in view of the present scenario, my answer to that question had to be no.

Although mortality from cancer is on the decrease in Europe, thanks to our increased understanding of the hallmarks of cancer, earlier diagnosis, and more powerful anti-cancer therapeutics, incidence is on the rise. In a recent paper published in the British Journal of Cancer, colleagues from Cancer Research UK (CRUK) forecast that one in two people will develop cancer at some point in their lives. The one in three has now alarmingly increased to two. This, coupled with an ever-increasing ageing population, translates into a daunting prospect over the next decades. We must therefore combine forces, working more closely with all oncology professions and stakeholders to ensure faster, streamlined results, a quicker development and implementation of targeted, more affordable treatment plans for an increasing number of our patients.

At the close of 2014, hot debate was sparked by a paper published in Science authored by Bert Vogelstein and colleagues at Johns Hopkins University School of Medicine. The study made headlines around the world as the Hopkins team concluded that a large proportion of cancer cases was attributed to "bad luck". Whatever conclusion you may draw, the major risk drivers of cancer are known. Adding to the mix is the so-called exposome -- environmental exposures that may contribute to increased probability of disease. This aspect of cancer research warrants much more attention even as we celebrate successes in the genomic profiling of patients' tumors.

Throughout 2014, VHIO has continued to up the tempo in its basic, translational and clinical research efforts by reinforcing current infrastructures, increasing its portfolio of technologies and clinical trials, as well as building upon cross-border partnerships. We have one collective goal in mind: to get the right treatment, to the right patient, at the right dose, at the right time. We are better equipping our teams to more precisely tackle the specificities of each individual cancer, across all tumor types, and thus respond to the many challenges and yet unanswered questions that still remain in our battle against cancer.

VHIO's cutting-edge technologies, tests, and platforms: powerful armory against cancer

Thanks to the dedicated work of our Cancer Genomics Group headed by Ana Vivancos, our pre-screening efforts for mutations in patients who are candidates for enrollment in our broad portfolio of Phase I clinical trials carried out at the Research Unit for Molecular Therapy of Cancer (UITM) - "la Caixa", led by Jordi Rodón's Early Clinical Drug Development Group -- have established VHIO as one of the few groups in Europe to run such a comprehensive program. Using a custom amplicon panel, VHIO-Card, we study mutations in 61 oncogenes and tumor supressors at the same time, across all tumor types. Ana's team screens for both known mutations as well as those for which there are novel targeted therapies in the drug development pipeline. By broadening the scope of mutations under study we unmask more mutated samples, thus opening up more possibilities for patient stratification.

Deciphering the molecular profile of each patient indicates his/her suitability for inclusion in a given clinical trial aimed at testing the usefulness of novel targeted therapies, such as PI3K, AKT, BRAF or MEK inhibitors. These endeavors are not only revolutionizing tumor classification but also increasingly impacting on how cancer treatment decisions are made.

Importantly, VHIO's pre-screening program currently analyses the tumors of some 1000 patients per year -- those individuals who have exhausted all other standard therapies and are in critical need of alternative treatment regimens. If we are to extend these efforts to an increasing number of patients, we will need to do so in collaboration. In this respect, I am proud to announce the VHIO-Catalan Institute of Oncology (ICO) Research Alliance. Representing the biggest clinical cancer care provider in Catalonia, this powerful collaboration incorporates four comprehensive cancer centers throughout the region, providing clinical care to some 16,000 patients on a yearly basis. Direct access to extended patient populations will undoubtedly provide essential insights to more rapidly translate research into more effective, targeted treatments and better practice for the future care of our deserving patients.

VHIO's suite of cutting-edge technologies and assays including the nCounter Nanostring and RNAseq platforms, coupled with the expertise of our Core Technology teams who both develop and implement these techniques, enable us to bring more detailed prognostics directly to the clinical setting, and further develop and validate the next generation of tests. 2014 marked the successful implementation of a clinically applicable gene expression based test, known as PAM 50, for the management of breast cancer patients. Significantly, our Translational Genomics Group led by Aleix Prat was the first to do so in Europe. Such pioneering efforts will continue to empower VHIO in significantly contributing to better-guided treatment decisions as well as improved outcomes for patients.

Liquid biopsy 'policing' of cancer: ready for prime time?

One of the main challenges of cancer is its complex genetic landscape coupled with its ability to outsmart and dodge potent anti-cancer therapeutics. The need to better monitor and predict its every move is critical if we are to improve outcomes for our patients and deliver on the promise of precision medicine.

In this emerging era of personalized medicine in cancer, research breakthroughs have now rendered biopsies more precise in detecting cancer mutations, tracking the evolution of disease and circulating tumor cells that drive metastasis, as well as predicting response to therapy. There is enormous excitement about liquid biopsies -- blood tests that can non-invasively reveal circulating tumor DNA that is released by tumor cells into the bloodstream. This circulating DNA contains vital signals, components and genetic information about what is actually occurring in the tumor, providing us with a much bigger picture regarding the specificities and status of the patient's cancer.

Of tremendous importance in improving detection and following cancer's every move, is that these blood-based biopsies also allow for serial samples in order to identify tumor genomic alterations not only in real time, but over time.

As this Scientific Report goes to print, as part of a collaboration with Merck Serono and Sysmex Inostics, we have just announced that VHIO will be the first academic test center of its kind to use in-house BEAMing liquid biopsy RAS biomarker technology. Initially we will use blood-based technology to evaluate patients with metastatic colorectal cancer at research level. Expected to receive its European Conformity approval (CE mark) in 2015, this RAS biomarker test promises a more precise treatment for metastatic colorectal cancer patients.

I see enormous potential for liquid biopsies, so much so that I think they could, in the near future, replace tumorsection analysis and expand the scope of personalized medicine for our patients. In short, the liquid biopsy undoubtedly represents a potent new contender in ourcurrent weaponry against cancer.

Synergies and the same score sheet: empowerment through collaboration

While our preclinical, translational and clinical research efforts are certainly translating into benefits for patients, we must continue to share our expertise -- and benefit from the knowledge of others -- through cross-border collaboration (click here for VHIO's participation in various Consortia of international excellence). Such global exchange of data and ideas is crucial not only in accelerating advances but also to avoid wasteful duplication of efforts.

Launched at a special press conference during the 2014 Congress of the European Society for Medical Oncology (ESMO) last Autumn, Cancer Core Europe is a unique partnership aimed at addressing the cancer care-cancer research continuum. This working consortium represents a critical mass of activity for the successful integration of all cancer care information, clinical research and outcome research, spearhead by the six founding partners and leading European comprehensive cancer centers: the Gustave Roussy Cancer Campus Grand Paris (Villejuif, France), Cambridge Cancer Centre (Cambridge, UK), Karolinska Institute (Stockholm, Sweden), Netherlands Cancer Institute - NKI (Amsterdam, The Netherlands), National Center for Tumor Diseases - DKFZ-NCT (Heidelberg, Germany), and VHIO.

This consortium marks a significant forward step in harnessing, storing and sharing an overwhelming wealth of data generated through the 'onco'omics, clinical trials, cancer science and medicine. The Cancer Core Europe's pooling and exchange of expertise, research findings, common platforms and processes, will empower researchers and clinicians to rapidly exploit this trove of biological insights and clinical data for the benefit of patients.

I also want to highlight the successes to date of the SPECTAcolor - Screening Platform for Efficient Clinical Trials Access in Colorectal Cancer. Set up in September 2013 and funded by a corporate social responsibility program of Alliance Boots, SPECTAcolor is an initiative set within the framework of the research program of the EORTC and is a unique undertaking as the first ever prospective, fully annotated tumor biobank and biomarker analysis platform for the genetic profiling of patients suffering from advanced colorectal cancer.

Implemented across 19 clinical centers located in nine countries throughout Europe, including VHIO, it has succeeded in recruiting over 500 patients. This promising start has demonstrated its viability to facilitate next-generation cancer clinical trials and that a logistically complex infrastructure in a multinational setting is achievable -- proving that where there is willing, there is certainly a way.

As dedicated partner, VHIO will continue to accrue patients at local level through the Vall d'Hebron University Hospital's Medical Oncology Department, as well as advance biomarker discovery aimed at the rapid development of novel therapies targeted to the needs of each individual colorectal cancer patient.

"We are told that talent creates its own opportunities. But it sometimes seems that intense desire creates not only its own opportunities, but its own talents"

- Eric Hoffer, American social writer and philosopher (1902-1983).

As Director of VHIO, I am extremely proud of our talented teams of excellence who work together across programs in order to ensure the tight connectivity and cross-talk necessary to carry out multidisciplinary and translational research and medical practice -- as is evidenced by the updates described by each group in this Scientific Report.

VHIO's leading scientists and physician-researchers are tirelessly advancing their research, and, as a reflection of excellence, continue to secure precious funding that fuels their efforts in combating cancer. As I noted in last year's Foreword, Horizon 2020 replaced the European Union Framework Programmes with the emphasis on frontier and interdisciplinary research with one of the topics favoring novel studies and clinical approaches supporting the optimization of available therapies, specifically drug repurposing. Since talent fosters opportunity, we are optimistic that our proposals will be suitably considered and ultimately rewarded through this European funding.

I would also like to personally thank our devoted institutional supporters, the Generalitat de Catalunya, FERO, the Fundació Bancària "la Caixa", the Fundación BBVA, with the invaluable support from the Fundació Privada Cellex, as well as VHIO's many other supporters, funding entities and agencies (click here).

VHIO will only deliver on its goal of accelerating the pace in advancing personalized and targeted therapies against cancer thanks to the public funding it receives, as well as through such generous support from private institutions, companies and individuals, all of whom share the intense desire and drive to ensure the clock continue to tick in our favor - against cancer. This collective ambition not only allows us to do what we at VHIO do best -- rapidly translate cancer discovery into real benefit at clinical level -- but it also fosters essential growth and expansion of our programs.

In this respect, I am delighted to confirm that we have now successfully recruited new talent and groups in areas including cancer immunology and immunotherapy that will join us in 2015 to lead novel research focused on areas such as the tumor microenvironment, immuno-oncology, and the development of immune-based personalized therapeutics. To flank our efforts aimed at integrating clinical translational research with genomics for precision cancer therapy, I am delighted that Rodrigo Dienstmann will be returning to VHIO from Sage Bionetworks, Fred Hutchinson Cancer Research Center, USA, to set up and lead VHIO's Oncology Data Science Group.

Mention of expansion cannot be made without updating on the status of our new home -- the CELLEX building. We are now ready to move in -- marking a new era in VHIO's translational trajectory. Providing the valuable space through which to grow, the new building will bring all our multidisciplinary teams together under the same roof to enhance collaboration and spur our dedicated efforts to combat cancer.

At VHIO, as we demonstrate year after year, we have the desire, the talent and the opportunity to raise the bar and set our ambitions even higher.

Josep Tabernero
Director
The Vall d'Hebron Institute of Oncology (VHIO)



Who we are and what we do/

VHIO’s Organigram 2014

In order to translate cancer discovery into real benefit for an increasing number patients, VHIO has, from the very outset, adopted a purely translational, multidisciplinary research model. Organized into four main programs – Preclinical, Translational, Clinical, and Core Technologies, our research focuses on understanding the fundamental biology of human cancer, from cellular and molecular biology and genetics through to therapeutics.

Its optimal organizational structure allows VHIO talents to continue to both anticipate and tackle the many unresolved questions in ultimately outsmarting the multifaceted, heterogeneous and complex disease that is cancer:



A little extra on how we did it in 2014/

Aside from the many highlights described by each of our groups in this report, we would like to underline a few other important factors and developments in 2014 that enabled us to further advance cancer discovery through the integration of translational science and clinical research within a multidisciplinary setting - - the winning formula behind what we do and how we do it at VHIO:



VHIO's translation towards precision oncology

Established in 2006, VHIO is a leading comprehensive cancer center of excellence where its scientists and research physicians adopt a purely translational research model, working together as multidisciplinary teams to both accelerate and advance personalized and targeted therapies against cancer.

Undertaking one of Spain's most dynamic cancer research programs, VHIO is dedicated to delivering on the promise of 'precision'medicine in oncology – turning cancer discovery into more effective treatments and better practice for the care of our patients.



Oncogenomics and pre-screening

At the core of VHIO's research activities lies our suite of cutting-edge core technology platforms which allow our expert teams to apply next-generation whole-genome sequencing for precision oncology as well as develop and improve existing applications to drive faster results. By sequencing panels of genes or entire genomes in cancer patients, we are now better equipped than ever before to identify specific molecular risk factors and gauge the potential efficacy of specific agents for individual patients. In parallel, these technologies (Hiseq2500, MiSeq, nCounter Nanostring), accelerate our research efforts of our preclinical, translational and clinical scientists, enabling the identification of mechanisms of resistance to targeted therapies, the study of clonal populations, as well as defining novel therapeutic opportunities based on mutation profiles.

Our Cancer Genomics Group leads VHIO's pre-screening program of mutations in patients who are candidates for our portfolio of Phase I clinical trials. Assessing the molecular make-up of each patient provide us with vital insights regarding the suitability for enrollment in clinical studies aimed at testing the efficacy of novel anti-cancer therapeutics. Our pre-screening efforts have already established VHIO as one of the few centers in Europe to run such a comprehensive program. We will be looking to expand our efforts to an increasing number of patients thanks to the VHIO - Catalan Institute of Oncology (ICO) Research Alliance, representing the biggest clinical care provider in Catalonia.

As also detailed in our Director's Foreword, VHIO, in collaboration with Merck Serono and Sysmex Inostics, will be the first academic test center of its kind to use in-house BEAMing liquid biopsy RAS biomarker technology. This technology will initially be employed to evaluate metastatic colorectal cancer patients at research level. Once it receives its European Conformity approval, envisaged in 2015, this technology will be extended to conventional routine care and to addtional tumor types.

BEAMing digital PCR/fl ow cytometry technology: set to empower VHIO's existing suite of cutting-edge technologies.

By bringing more detailed prognostics directly to the clinical setting, and further developing and validating the next generation of tests, VHIO will significantly contribute to better guided treatment decisions as well as improved outcomes for patients, real time -- over time.



Clinical trials at VHIO: driving drug development and targeted therapies against cancer

VHIO has increasingly established itself as a leading reference in drug discovery from concept to the clinic. It has been able to do so not only through the bridging and tight connectivity between health care professionals, VHIO scientists and physician researchers but also through its Research Unit for Molecular Therapies of Cancer (UITM) "la Caixa" located in the patient care environment of the Vall d'Hebron University Hospital, and set within the research context, as well as the Clinical Trials Office of the same hospital.

Research at the UITM is led by VHIO's Early Clinical Drug Development Group, focusing on both the development of new drugs based on the molecular profile of each tumor as well as the optimization of treatment regimens using combinations of new drugs with existing ones. In 2014, 83 Phase I clinical trials were performed at the Unit, with a total of 303 patients enrolled. The Clinical Trials Office coordinates a large portfolio of Phase I – II – III studies and consistently reports an increase in the number of trials conducted each year. In 2014 the number of patients included in our studies totaled at 771 across 246 trials.

In December 2014, in recognition of the support we receive from the Fundació Bancària "la Caixa" and the tremendous successes marked since the UITM was inaugurated in 2010, we hosted and celebrated a joint press conference. Attended by some 20 leading journalists throughout Spain, the conference also counted on the participation of two of our wonderful patients who related their respective patient journeys as well as addressed the many questions put directly to them by the media.



VHIO's direct access to cancer patients: a critical asset in VHIO's purely translational research model

As evidenced throughout this report, across our preclinical, translational and clinical research programs, VHIO's talents continue to advance cancer discovery and medicine (click here for our full list of publications in 2014, and an overview of scientific productivity as well as selected articles click here). Our research endeavors largely benefit from VHIO's privileged location within the heart of the Vall d'Hebron University Hospital, affording direct access to patients as well as the entire spectrum of oncology patients who care for them. Organized into multidisciplinary integrated teams, our researchers closely collaborate and interact with Vall d'Hebron physician-scientists. Translational science and clinical research are therefore tightly connected, accelerating the bench-bedside-bed cycle of knowledge.

The Vall d'Hebron University Hospital: the largest hospital complex in Catalonia and one of the most important in Spain.



Cancer research at VHIO: dismantling cancer's armory

Commandeering research aimed at combating cancer, our preclinical, translational and clinical researchers as corresponding/senior authors or co-authors, published 170 scientific articles in 2014 (83% Q1), with a cumulative Impact Factor totaling at 1551.677, and a Median Impact Factor (MIF) of 9.13. These figures reflect an increase in scientific productivity, maintained MIF score, as well as the importance of VHIO's research and contribution to the oncology field.

For the complete list of articles published by VHIO researchers and physician-scientists in 2014 click here. To view this year's selection of just some of the most relevant articles by VHIO Faculty published in 2014, click here.



VHIO's participation in consortia and networks of excellence

To accelerate discovery and thus improved cancer treatment and care, we are committed to combining strengths and overcoming current obstacles in collaboration. Such strategic cross-border alliances and partnerships will undoubtedly help to spur advancements rendering personalized medicine more precise and accessible for an increasing number of cancer patients.

In addition to VHIO's continued participation in some of the most forward-thinking, inspired and pioneering consortia at international level (click here), 2014 witnessed its partnering with the Cancer Core Europe working consortium:

Powered by the six founding partners, the Gustave Roussy Cancer Campus Grand Paris (Villejuif, France), Cambridge Cancer Centre (Cambridge, UK), Karolinska Institute (Stockholm, Sweden), Netherlands Cancer Institute - NKI (Amsterdam, The Netherlands), National Center for Tumor Diseases - DKFZ-NCT (Heidelberg, Germany), and VHIO, this unique undertaking represents a transformative initiative whereby leading cancer comprehensive cancer centers will work collectively to address the cancer care – cancer research continuum.

Since the optimal treatment of cancer remains one of the major medical challenges globally due to the high diversity in the spectrum of mutations in individual cancer patients, among many other implicated factors, Cancer Core Europe will drive towards better integrated cancer programs performed at large scale.

Yearly within the Cancer Core Europe Consortium around 60.000 newly diagnosed cancer patients are seen, 300.000 cancer treatments are delivered, around 1.000.000 outpatient visits are performed, and more than 1.500 clinical trials are being conducted across the six cancer centers. Together with the strengths in basic and translational cancer research, this represents a unique critical mass of activity than once successfully harmonized as one operational research structure, will constitute a major force in European cancer science and clinical care.

For all forthcoming Cancer Core Europe updates and news please bookmark and visit VHIO's website:

www.vhio.net



Other collaborative opportunity in 2014

2014 also marked the exciting launch of a regionally-based multi-center bioinformatics platform as part of a joint initiative of the Government of Catalonia and the Fundació Bancària "la Caixa". VHIO joined 43 other partners incorporating research centers and clinical institutes, universities, pharmaceutical and IT companies, among others to support and participate in the Bioinformatics Barcelona (BIB) platform.

BIB will establish itself as a central point and facilitator of new initiatives to respond to the needs of the bioinformatics community. By capitalizing on the critical mass of like-minded, internationally renowned researchers, currently available IT infrastructures, and an entire network of biotech companies, the platform will strive to become an international reference within the bioinformatics field.

For more information visit:

www.bioinformaticsbarcelona.eu

Throughout 2014, based on common synergies and a shared forward-thinking with several other leading research entities at global level, we have been paving the way for future collaborations and key alliances - - to be announced in next year's Scientific Report, 2015.



The CELLEX building: marking a new era in VHIO's translational trajectory

Providing the valuable space through which to grow, the new building will bring all our multidisciplinary teams together under the same roof to enhance collaboration and spur our dedicated efforts to combat cancer. As this Scientific Report goes to print, we are now ready to move into our new premises.

With the invaluable support from:



VHIO-organized events: stimulating thoughtprovoking, two-way exchange

In 2014 VHIO opened its doors to participants at the following events:



• VHIO's annual series of Meet the Editors

Our VHIO Meet the Editors prestigious talks continued to provide oncology professionals of research institutes of excellence in Barcelona with unique opportunity to learn more about scientific publishing and cancer research and put questions and comments to the editors directly during the Q & A with the audience. They also continued to provide valuable opportunity to get to know the editors of the highest impact factor journals personally:

VHIO Meet the Editors in 2014:

Speaker: Judy Quong, Executive Editor of Cancer Discovery
Talk: Cancer Discovery: Looking Back, Moving Forward
Date: 24 February 2014

Speaker: Jean-Charles Soria, Editor-in-Chief, Annals of Oncology
Talk: Annals of Oncology: an Editorial Perspective
Date: 08 September 2014



• The Weizmann Institute of Science and VHIO: a powerful duo in advancing insights into Cellular Communication in Translational Research

Jointly organized by the Weizmann Institute of Science (WIS) and VHIO, a two-day must-have conversation on Cell Communication in Translational Research: bringing basic research into the clinic, 22 – 23 January 2015, Rehovot, Israel, will not only provide a platform through which to share and debate the latest research aimed at combating cancer, but also endorse the strengths and synergies between WIS and VHIO.

To be hosted by WIS, the meeting incorporates an outstanding panel of speakers cherry-picked by scientific Co-Chairs Irit Sagi, Principal Investigator, Department of Biological Regulation, and Dean of the Fienberg Graduate School at WIS, and Joaquín Arribas, Director of Preclinical Research at VHIO.

Internationally renowned experts from among WIS and VHIO Faculty, as well as other leading research institutes from Spain, have been specially selected not only for their respective areas of expertise in the realm of cell communication in cancer, but also for their shared dedication and drive towards translating and accelerating cancer discovery at preclinical level into real benefit for cancer patients. Engineered to report on pioneering research into cancer molecular mechanisms and efforts towards precision cancer science and medicine, the conference has been purposely devised to encourage the active participation of our up-coming talents in the oncology -- our young scientists and physician-researchers.

It is thanks to the generosity of the following WIS-VHIO meeting sponsors that we will be able to share latest insights with colleagues and peers, as well as explore possible new avenues for collaboration: Mr. David Gebler, Madrid, Spain, Casa Cresques Barcelona Israeli-Catalan Hub, The Weizmann Institute of Science, The Weizmann Institute of Science Feinberg Graduate School, The Nancy & Stephen Grand Israel National Center for Personalized Medicine, Conferences and Schools Program, WIS-CSP, and VHIO.

To discover more about this WIS-VHIO exploration into the breakdown of cell communication, the consequential cancer growth and spread, and promising therapeutic avenues against it, visit: wws.weizmann.ac.il/conferences/CCTR2015/.



• VHIO ad-hoc Courses, Workshops & Observerships

Based on specific research lines and areas that have successfully established VHIO as a leading international reference, we share our expertise, learn from eminent guest speakers, discuss and debate our latest findings through the organization of VHIO ad-hoc courses and workshops as well as VHIO Faculty attendance at International Cancer Conferences.



Contact: +34 93 489 30 21 Email: info@vhio.net    |    © Vall d'Hebron Institute of Oncology (VHIO)    |    Photography: Katherin Wermke