"Our Program, incorporating multidisciplinary cancer teams, develops novel agents and approaches to diagnose cancer earlier and better predict response to therapy. Pioneering studies involving both preclinical and early-drug development discovery, we also lead several clinical trials designed to render anti-cancer therapies more precise."
Associate Translational Investigator
Medical Oncologists and Clinical Fellows
José Manuel Pérez
Mª Jesús Vidal
Our Breast Cancer Program continues to be one of the most active in Spain and one of the most renowned across Europe. In 2015, 32 publications (18 of them in the first quartile), totaled an Impact Factor (IF) of 383,45 with a mean IF of 11,98. Interestingly, we published two articles in the New England Journal of Medicine this year, a highly prestigious publication renowned for publishing practice changing data in biomedicine. In both studies, VHIO’s authors were also involved in the design of the respective trials.
This year we have initiated more than 15 new clinical trials and studies. Our group is not only committed to participating in clinical and preclinical studies, but also leads several of them -- reflected by our representation of Steering Committees for some, and appointed international leaders for others.
Our main areas of interest continue to center on the development of novel therapies and the search for mechanisms of resistance to current agents. Multidisciplinary collaboration with surgeons, pathologists, radiologists and radiotherapists, among other disciplines, facilitates the incorporation of the most innovative treatments in clinical practice and optimizes therapeutic alternatives. In clinical research, our key areas of activity include:
Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortés J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734.
Francis PA, Regan MM, Fleming GF, Láng I, Ciruelos E, Bellet M, Bonnefoi HR, Climent MA, Da Prada GA, Burstein HJ, Martino S, Davidson NE, Geyer CE Jr, Walley BA, Coleman R, Kerbrat P, Buchholz S, Ingle JN, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Colleoni M, Viale G, Coates AS, Goldhirsch A, Gelber RD; SOFT Investigators; International Breast Cancer Study Group. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015;372(5):436-446.
De Mattos-Arruda L, Mayor R, Ng CK, Weigelt B, Martínez-Ricarte F, Torrejon D, Oliveira M, Arias A, Raventos C,Tang J, Guerini-Rocco E, Martínez-Sáez E, Lois S, Marín O, de la Cruz X, Piscuoglio S, Towers R, Vivancos A, Peg V, Cajal SR, Carles J, Rodon J, González-Cao M, Tabernero J, Felip E, Sahuquillo J, Berger MF, Cortes J, Reis-Filho JS, Seoane J. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun. 2015;6:8839.
Lin L; Sabnis AJ; Chan E; Olivas V; Cade L; Pazarentzos E; Asthana S; Neel D; Yan JJ; Lu X; Pham L; Wang MM; Karachaliou N; Cao MG; Manzano JL; Ramirez JL; Torres JM; Buttitta F; Rudin CM; Collisson EA; Algazi A; Robinson E; Osman I; Muñoz E; Cortes J; Frederick DT; Cooper ZA; McMahon M; Marchetti A; Rosell R; Flaherty KT; Wargo JA; Bivona TG. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet. 2015;47(3):250-256.
Principal Investigator, Early Clinical Drug Development Group, Director & Medical Coordinator, UITM
Director of Clinical Research at VHIO
PHASE I RESEARCHERS
Analía B. Azaro
María Elena Élez
Ana Garrido Castro
Maria Ochoa de Olza
Jose Manuel Pérez
Our main interest surrounds proof-of-concept and proof-of-mechanism trials with targeted therapies, especially those aimed at cell signaling, cancer stem cells and immuno-oncology. These include firstin-human studies of targeted therapies, rational combinations of targeted therapies, biomarker-driven trials, and trials in molecularly selected populations.
We try to link clinical research at the UITM with the different areas of research carried out at VHIO, following a truly translational model: linking molecular biology and the best tumor models with pharmacology and innovative clinical research. We are therefore dedicated to involving VHIO scientists in our trials (biomarker development, profound understanding of mechanisms of action and resistance) for selected projects. We have collaborated with VHIO’s Molecular Oncology Group, headed by Paolo Nuciforo, as well as the Cancer Genomics Group led by Ana Vivancos, to perform molecular analysis of patients’ tumors in order to select the best possible treatment for our patients with the experimental therapies available in our portfolio of clinical trials - one step closer to realizing the true promise of precision medicine. Importantly, in relation to precision oncology, VHIO is a founding member of the WIN (Worldwide Innovative Networking in personalized cancer medicine) and the Cancer Core Europe Consortia. Both are nongovernmental organizations that bring together international (WIN) and/or European (CCE) cancer centers including VHIO to advance cancer diagnostics and therapeutics, especially in the area of precision medicine.
We are expanding our expertise in immuno-oncology with a large portfolio of trials covering some of the most promising targets in immune checkpoints and cytokines. We are also converging immuno-oncology and genomics to further enhance and expand precision medicine against cancer.
Rodon J, Carducci MA, Sepulveda-Sánchez JM, Azaro A, Calvo E, Seoane J, Braña I Sicart E, Gueorguieva I, Cleverly AL, Pillay NS, Desaiah D, Estrem ST, Paz-Ares L, Holdhoff M, Blakeley J, Lahn MM, Baselga J. First-in.human dose study of the novel transforming growth factor-b receptor I kinase inhibitor LY2157299 monohydrate in patients with advanced cancer and glioma. Clin Cancer Res. 2015;21(3):553-560.
Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria JC. Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol. 2015;33(30):3401-3408.
Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in Multiple Nonmelanoma Cancers with BRAFV600 Mutations. N Engl J Med. 2015;373(8):726-736.
Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689-1699.
Medical Oncologists and Clinical Fellows
María Elena Élez
Clinical Nurse Specialist
In 2015, we have led and participated in numerous cooperative and singular research projects related to Gastrointestinal Malignancies. In addition to our key participation in existing international consortia of excellence including Cancer Core Europe and the FP-7 supported COLTHERES, EurocanPlatform, and MerCuRIC Consortia, I am delighted to announce that 2015 celebrated the launch of the MoTricolor Consortium. Spurred by EU’s Horizon 2020 program, and led by VHIO, this pan-European project will design and lead Molecularly guided Trials with specific treatment strategies in patients with advanced newly molecular defined subtypes of Colorectal cancer, and for the first time, stratify patients based on their gene expression profiles according to recently established predictive signatures. We will collectively aim to identify sensitivity of individual patients to the proposed experimental therapies towards ultimately developing more precise anti-cancer therapies.
Reflected by publications in the most prestigious scientific titles in 2015, our group has also led and collaborated in studies with important clinical implications, just some of which include:
We continue to develop next generation blood-based diagnostics to monitor disease, its respective molecular specificities, and response to novel targeted therapies. Findings from the first large clinical trial to compare liquid versus conventional tissue biopsy data, the CORRECT phase III study, showed that BEAMing technology produced more data on tumor mutation throughout the course of the disease (Tabernero J. et al. 2015. Lancet Oncol. 16: 937-948).
Lastly, our group has participated in several pre-clinical and clinical studies on predicted responsive patient subsets using genetically annotated tumor surgical specimens (‘Xenopatients’) in mice, further expanding our collaboration with VHIO’s Stem Cells & Cancer Group.
Mayer RJ; Van Cutsem E; Falcone A; Yoshino T; Garcia-Carbonero R; Mizunuma N; Yamazaki K; Shimada Y; Tabernero J; Komatsu Y; Sobrero A; Boucher E; Peeters M; Tran B; Lenz HJ; Zaniboni A; Hochster H; Cleary JM;Prenen H; Benedetti F; Mizuguchi H; Makris L; Ito M; Ohtsu A. Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N Engl J Med. 2015;372(20):1909-1919.
Hyman DM; Puzanov I; Subbiah V; Faris JE; Chau I; Blay JY; Wolf J; Raje NS; Diamond EL; Hollebecque A; Gervais R; Elez E; Italiano A; Hofheinz RD; Hidalgo M; Chan E; Schuler M; Lasserre SF; Makrutzki M; Sirzen F; Veronese ML; Tabernero J; Baselga J. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med. 2015;373(8):726-736.
Tabernero J; Yoshino T; Cohn AL; Obermannova R; Bodoky G; Garcia-Carbonero R; Ciuleanu TE; Portnoy DC; Van Cutsem E; Grothey A; Prausová J; Garcia-Alfonso P; Yamazaki K; Clingan PR; Lonardi S; Kim TW; Simms L; Chang SC; Nasroulah F. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499-508.
Elez E; Kocáková I; Höhler T; Martens UM; Bokemeyer C; Van Cutsem E; Melichar B; Smakal M; Csoszi T; Topuzov E; Orlova R; Tjulandin S; Rivera F; Straub J; Bruns R; Quaratino S; Tabernero J. Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial. Ann Oncol. 2015;26(1):132-140.
Medical Oncologists and Clinical Fellows
Our group is interested in both clinical and translational research with broad experience and grounded expertise in the treatment of different neoplasms. We design and develop clinical trials for genitourinary malignancies at different stages of disease in collaboration with urologists and radiation therapists.
Over recent years, many developments have been reported in GU tumors; particularly in prostate, bladder and kidney cancer. Immunotherapy is proving increasingly important in the treatment of bladder and kidney cancer. We have been able to participate in different clinical trials using checkpoint inhibitors. Close collaboration with all specialists involved in the treatment of these tumors is consequently essential. We are also focused on the continued development of our translational research platform for urologic cancer, as well as conducting clinical trials in early, adjuvant as well as metastatic disease.
Our group collaborates with other research centers of excellence including the Cleveland Clinic (USA), University of California San Francisco (USA), Gustave Roussy Hospital (France), and the Biomedical Research Institute of Bellvitge (IDIBELL), here in Barcelona (Spain). We have developed the avatar program for kidney cancer tumors in collaboration with IDIBELL and have now implanted more than 20 samples. Another key area is the development of several multidisciplinary clinical studies and phase I trials in CNS tumors, in close collaboration with professionals in neurosurgery and radiation therapy. We are also dedicated to expanding our translational research platform for glioblastoma in collaboration with VHIO’s Gene Expression & Cancer Group led by Joan Seoane. We have consolidated a collaborative study with different centers across Europe to develop a vaccine for patients with glioblastoma and we are now initiating the phase I program. This project is supported by the European Commission’s 7th Framework Programme of Research and Development.
Our group works closely with the Spanish Sarcoma Group (GEIS) to conduct clinical trials at different stages of disease with emphasis on a histology-tailored design. We are currently setting up a translational platform for sarcomas and basic research in partnership with IDIBELL and the Cancer Research Center of Salamanca (CIC – Spain). For GIST tumors we work in partnership with J. Fletcher’s lab at Brigham and Women’s Hospital (USA).
Cesar Serrano joined our group as VHIO researcher in 2014 having spent the previous three years at Brigham and Women’s Hospital. He was awarded a Grant from the SARC (Sarcoma Alliance for Research through Collaboration) to develop new therapies against GIST tumors. We are currently developing novel strategies in GIST therapy in close collaboration with other referral centers throughout Europe and pharmaceutical companies.
The serum bank has expanded to include the majority of our tumor types (CNS tumors, GIST; renal cell carcinoma and CRPC) and will continue to recruit samples from our patients. Importantly in terms of education and exchange, in 2015 we welcomed five fellows from in and out Spain to visit our group for short stays of three months.
Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, Carles J, Flaig TW, Taplin ME, Higano CS, de Souza P, de Bono JS, Griffin TW, De Porre P, Yu MK, Park YC, Li J, Kheoh T, Naini V, Molina A, Rathkopf DE; COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-60.
Smith MR, Rathkopf DE, Mulders PF, Carles J, Van Poppel H, Li J, Kheoh T, Griffin TW, Molina A, Ryan CJ. Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naïve Patients with Metastatic Castration Resistant Prostate Cancer. J Urol. 2015;194(5):1277-1284.
Climent MÁ, León-Mateos L, González Del Alba A, Pérez-Valderrama B, Méndez-Vidal MJ, Mellado B, Arranz JÁ, Sánchez-Hernández A, Cassinello J, Olmos D, Carles J. Updated recommendations from the Spanish Oncology Genitourinary Group for the treatment of patients with metastatic castration-resistant prostate cancer. Crit Rev Oncol Hematol. 2015;96(2):308-318.
De Mattos-Arruda L, Mayor R, Ng CK, Weigelt B, Martínez-Ricarte F, Torrejon D, Oliveira M, Arias A, Raventos C, Tang J, Guerini-Rocco E, Martínez-Sáez E, Lois S, Marín O, de la Cruz X, Piscuoglio S, Towers R, Vivancos A, Peg V, Ramon y Cajal S, Carles J, Rodon J, González-Cao M, Tabernero J, Felip E, Sahuquillo J, Berger MF, Cortes J, Reis-Filho JS, Seoane J. Cerebrospinal fluid-derived circulating tumour DNA better represents the genomic alterations of brain tumours than plasma. Nat Commun. 2015;6:8839.
In 2016 we aim to consolidate clinical research in the Sarcoma field and progress in the treatment of GIST. We will also seek to accelerate tailored treatments in GU malignancies and CNS tumors with the goal of developing our translational research in both tumor types:
We hope to further increase our participation in phase I trials carried out at the Research Unit for Molecular Therapy of Cancer UITM - "la Caixa". These superb facilities allow new studies on innovative drugs and therapeutic leads to improve the pharmacological treatments for cancer and reduce their toxicity.
Medical Oncologist and
Our group mainly focuses on clinical research in gynecological malignancies. We are majorly involved in the development of new therapies in the treatment of gynecologic tumors. Notably, our clinical research work has led to approval of new standard of care in both resistant relapsed ovarian cancer ( e.g. AURELIA Trial) and in metastatic cervical cancer (e.g. GOG240 trial).
Our clinical research is largely developed through our close collaboration with other international renowned research groups of excellence. We are active members of some of the most relevant societies in gynecological oncology including the Gynecologic Cancer Inter Group (GCIG) serving as the Spanish Representative on the Cervical Cancer Committee, the Gynecologic Oncology Group (GOG) as Spanish Clinical lead, as well as the European Network of Gynecological Oncology Trial Groups (ENGOT). In addition, our group’s PI, Ana Oaknin serves on the Executive Board as Vice President for the Grupo Español de Investigación en Cáncer de Ovario (Spanish Gynecological Group - GEICO). Such involvement allows us to initiate the development of new drugs and novel treatment approaches from the very outset, which in turn, provides our patients with greater opportunity to potentially benefit from these research efforts.
It is thanks to our strong and expanding clinical research endeavors aimed at advancing treatment and care for gynecological tumors, coupled with our established reputation for excellence, that we serve as a Reference Site for the majority of regional hospitals and sites at national level. This position of leadership has consequently led to a steady increase in the number of patients treated with new therapies in our clinical trials and, most importantly, provided new hope for these patients.
We are currently leading clinical studies with novel PARP inhibitors for both patients with ovarian cancer associated to the BRCA mutation as well as a welldefined group of patients with high grade ovarian carcinoma. These new drugs have the potential to change the course of history in the treatment of ovarian cancer since they act at specific molecular points in DNA repair pathways. Our group also has a keen interest in immunotherapy and angiogenesis.
In parallel with our clinical research, we play a central and key role as members of multidisciplinary committees and teams in Gynecological Cancer Tumors at the Vall d’Hebron University Hospital (HUVH). Our involvement, in close connectivity and collaboration with other professionals and specialties (including surgeons, radiotherapists, radiologists and pathologists), contributes to establishing new treatment protocols and clinical guidelines to further advance clinical practice within our Hospital.
We are continuously invited to participate at international conferences of excellence through the delivery of presentations, invited lectures, and the sharing and debating of key findings with colleagues and peers across the globe.
McMeekin S, Dizon D, Barter J, Scambia G, Manzyuk L, Lisyanskaya A, Oaknin A, Ringuette S, Mukhopadhyay P, Rosenberg J, Vergote I. Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer. Gynecol Oncol. 2015;138(1):18-23.
Penson RT, Huang HQ, Wenzel LB, Monk BJ, Stockman S, Long HJ 3rd, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ1, Leitao MM, Method M, Michael H, Tewari KS3. Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240). Lancet Oncol. 2015;16(3):301-311.
Amit M Oza, David Cibula, Ana Oaknin, Christopher Poole, Ron H J Mathijssen, Gabe S Sonke, Nicoletta Colombo, Jiří Špaček, Peter Vuylsteke, Holger Hirte, Sven Mahner, Marie Plante, Barbara Schmalfeldt, Helen Mackay, Jacqui Rowbottom, Elizabeth S Lowe, Brian Dougherty, J Carl Barrett, Michael Friedlander. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol. 2015;16(1):87-97.
Oaknin A, Rubio MJ, Redondo A, De Juan A, Cueva Bañuelos JF, Gil-Martin M, Ortega E, Garcia-Arias A,Gonzalez-Martin A, Bover I. SEOM guidelines for cervical cancer. Clin Transl Oncol. 2015;17(12):1036-1042. Epub 2015 Dec 9.
Clinical Nurse Specialist
We are committed to developing new targeted therapies for patients with hereditary breast cancer. During 2015, patients with local and advanced breast cancer and a BRCA germline mutation participated in several phase II/III trials with a specific DNA binding agent or PARP inhibitor. Consolidation of our collaboration with other VHIO groups led by Violeta Serra, Ana Vivancos, and Orland Díez, has resulted in a large collection of BRCA-associated patientderived xenografts implanted in athymic mice. These murine models are being used to identify mechanisms of resistance to targeted therapies, identify novel biomarkers, and test new combinatorial treatments at progression.
In the field of genetic epidemiology we are mainly focused on identifying new genetic susceptibilities to hereditary breast cancer. We are collaborating with VHIO’s Oncogenetics Group headed by Orland Díez on next generation sequencing studies with a panel of 98 cancer susceptibility genes in breast cancer families with no mutation in BRCA1/BRCA2. Analysis of the first 120 families has provided 9 genetic results with clinical utility. We are committed to performing cosegregation analysis in these families and investigating the cancer spectrum and phenotype of these lesser-known non-BRCA genes. In hereditary colorectal cancer we are participating in a study to identify mutations in POLD1 and POLE in families with polyposis, or young-onset colorectal cancer with microsatellite stability; and we are participating in a national registry led by the EPICOLON group to describe the characteristics of extracolonic tumors in Lynch syndrome mutation carriers.
Our group continues to actively participate in the international multi-center IMPACT study to analyze the efficacy of early detection of prostate cancer in patients with a mutation in the BRCA1/2 genes, as well as an additional study aimed at the characterization of prostate cancer in BRCA and MMR-deficient mutation carriers.
Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250.
Balmaña J, Domchek SM. BRIP1 as an ovarian cancer susceptibility gene: ready for the clinic? J Natl Cancer Inst. 2015;107(11).
Kastrinos F, Ojha RP, Leenen C, Alvero C, Mercado RC, Balmaña J, Valenzuela I, Balaguer F, Green R, Lindor NM, Thibodeau SN, Newcomb P, Win AK, Jenkins M, Buchanan DD, Bertario L, Sala P, Hampel H, Syngal S, Steyerberg EW; Lynch Syndrome prediction model validation study group. Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer. J Natl Cancer Inst. 2016;108(2). Epub 2015 Nov 18.
Domchek SM, Aghajanian C, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Loman N, Robertson JD, Mann H, Kaufman B. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199-203. Epub 2015 Dec 23.
We focus on two main lines of research: 1) the genetic predisposition to hereditary cancer, and 2) genetic predisposition to radiotherapy-induced toxicity.
Inherited predisposition to breast and ovarian cancer is caused mainly by BRCA1, BRCA2, PALB2, RAD51C, TP53, as well as some other genes. We search for other alleles that may predispose to these types of cancer using massive sequencing technologies to study panels of potentially predisposing genes. Moreover, we analyze whole exomes to discover new genes that could explain the presence of multiple cancers in families and individual patients.
BRCA1/2 genes have an extraordinary high allelic heterogeneity and many results of genetic testing are variants with unknown clinical significance (VUS). The analysis of these variants and other alterations in untranslated regions in both genes constitutes another area of intensive study. We carry out splicing studies, in silico analyses, and collaborate with other partners in international consortia (ENIGMA) to develop multifactorial studies aimed at ascertaining the effect of VUS. We are also working to establish a biological model through which to evaluate the in vitro functional effect of VUS and determine their potential pathogenicity.
Similarly, in collaboration with the Vall d’Hebron Research Institute’s (VHIR) Translational Bioinformatics Group headed by X. de la Cruz, we are actively participating in the development of a novel in silico tool to evaluate the effect of BRCA1/2 genetic variants identified in patients with cancer predisposition.
During 2015, we initiated a project (PI: Cristina Cruz) in collaboration with VHIO’s High Risk & Cancer Prevention and Experimental Therapeutics Groups, headed by Judith Balmaña and Violeta Serra respectively, to analyze the role of expression changes in new or natural BRCA1 mRNA isoforms as a mechanism of resistance to PARP inhibitors, using patient-derived tumor xenografts (PDXs).
Around half of all cancer patients receive radiotherapy at some point during the course of their treatment and between 3-5% of these patients suffer from severe long-term side-effects. Current evidence suggests the heritability of radiosensitivity, triggering growing interest in identifying the genetic variants associated with increased sensitivity to radiation. To identify those patients who will develop toxicity, we are investigating potential genetic and cellular markers for radiotherapy toxicity (allelic variants, cell apoptosis, and transcriptional profiles). In collaboration with the International Consortium of Radiogenomics we have participated in a meta-analysis showing an association between the ATM rs1801516 SNP and toxicity post-radiotherapy.
Fuentes-Raspall MJ, Caragol I, Alonso C, Ramón Y Cajal T, Fisas D, Seoane A, Carvajal N, Bonache S, Díez O, Gutiérrez-Enríquez S. Apoptosis for prediction of radiotherapy late toxicity: lymphocyte subset sensitivity and potential effect of TP53 Arg72Pro polymorphism. Apoptosis. 2015;20(3):371-382.
Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A, Shen HC, Beesley J, …, the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat Genet. 2015;47(2):164-171.
Rebbeck TR, Mitra N, Wan F, Sinilnikova OM, Healey S, McGuffog L, et al. Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA. 2015;313(13):1347-1361.
Eccles D, Mitchell G, Monteiro ANA, Schmutzler R, Couch FJ, Spurdle AS, Gómez-García EB, on behalf of the ENIGMA Clinical Working Group. BRCA1 and BRCA2 genetic testing – pitfalls and recommendations for managing variants of uncertain clinical significance. Ann Oncol. 2015;26(10):2057-2065.
Clinical Research Postdoctoral Fellowship
Recipient: Sandra Bonache
Agency: Fundación AECC Investigación contra el Cáncer
Short-Stay Grant for visiting the Molecular Cancer Epidemiology group at QIMR Berghofer Medical Research Institute, Australia (head: Dr. Amanda Spurdle)
Recipient: Gemma Montalban
Agency: FundacióMontcelimar - Universitat de Barcelona
Duration: September 2015-November 2015
VHIO’s Oncology Data Science (ODysSey) Group provides guidance to medical oncologists and cancer biologists during the development, validation and interpretation of “omics”-based tests that have direct clinical application. Our main objective is to provide researchers with reliable tools to investigate biomarkers developed to optimize patient stratification, based on differences in response patterns to cancer therapies or outcome.
To do so, we design and maintain clinical-molecular databases, integrating the results of “multi-omics” tumor profiling tests performed at VHIO with information available in electronic medical records, including treatment benefit and patient survival across multiple tumor types. This represents a critical resource for medical oncologists, molecular pathologists and translational investigators at VHIO studying predictive and prognostic biomarkers. We also manage the Gene Drug Knowledge Database (GDKD) (doi:10.7303/syn2370773), a structured database that uses standardized terminology to describe associations linking different layers of annotations: tumor types, genes, variants, response/resistance patterns to approved and experimental agents under clinical investigation, and PubMed identifiers.
We also encourage and promote collaborative research among computational oncology scientists on predictive and prognostic modeling, identification of cancer drivers, intra-tumor heterogeneity and druggability in solid tumors.
Dienstmann R, Jang IS, Bot B, Friend S, Guinney J. Database of genomic biomarkers for cancer drugs and clinical targetability in solid tumors. Cancer Discov. 2015;5(2):118-123.
Dienstmann R, Salazar R, Tabernero J. Personalizing colon cancer adjuvant therapy: selecting optimal treatments for individual patients. J Clin Oncol. 2015;33(16):1787-1796.
Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, Roselló S, Tops BB, van der Post RS, Argilés G, Skartved NJ, Hansen UH, Hald R, Pedersen MW, Kragh M, Horak ID, Braun S, Van Cutsem E, Tolcher AW, Tabernero J. Safety and activity of the first-in-class Sym004 anti-EGFR antibody mixture in patients with refractory colorectal cancer. Cancer Discov. 2015;5(6):598-609.
Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, Marisa L, Roepman P, Nyamundanda G, Angelino P, Bot BM, Morris JS, Simon IM, Gerster S, Fessler E, De Sousa E Melo F, Missiaglia E, Ramay H, Barras D, Homicsko K, Maru D, Manyam GC, Broom B, Boige V, Perez-Villamil B, Laderas T, Salazar R, Gray JW, Hanahan D, Tabernero J, Bernards R, Friend SH, Laurent-Puig P, Medema JP, Sadanandam A, Wessels L, Delorenzi M, Kopetz S, Vermeulen L, Tejpar S. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350-1356.
Our group is integrated within the Radiation Oncology Department of the Vall d’Hebron University Hospital (HUVH) and is actively involved in the multidisciplinary treatment of patients with malignant tumors. We also participate as principal investigators or research collaborators in a number of important clinical trials, translational research projects, as well as technology development programs.
Current and future research priorities include the following key areas:
Giralt J, Trigo J, Nuyts S, Ozsahin M, Skladowski K, Hatoum G, Daisne JF, Yunes Ancona AC, Cmelak A, Mesía R, Zhang A, Oliner KS, VanderWalde A. Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial. Lancet Oncol. 2015;16(2):221-232.
Mesía R, Henke M, Fortin A, Minn H, Yunes Ancona AC, Cmelak A, Markowitz AB, Hotte SJ, Singh S, Chan AT, Merlano MC, Skladowski K, Zhang A, Oliner KS, VanderWalde A, Giralt J. Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncol. 2015;16(2):208-220.
Zapatero A, Guerrero A, Maldonado X, Alvarez A, Gonzalez San Segundo C, Cabeza Rodríguez MA, Macias V, Pedro Olive A, Casas F, Boladeras A, de Vidales CM, Vazquez de la Torre ML, Villà S, Perez de la Haza A, Calvo
FA. High-dose radiotherapy with short-term or long-term androgen deprivation in localized prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16(3):320-327.
Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, Schulten J, Ang KK, Bonner JA. Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab. J Clin Oncol. 2016;34(12):1300-1308. Epub 2015 Dec 28.
Non Funded Projects
The main focus of the Thoracic Tumors & Head and Neck Cancer Group is to tackle various aspects of lung cancer, the most frequently diagnosed tumor to date. Our group concentrates on a number of areas ranging from disease prevention, early detection, more accurate techniques in diagnosis and staging to advancing precision medicine and treatment of lung cancer. We are also highly dedicated to our program which focuses on targeted therapies in patients with specific molecular alterations and immunotherapy strategies.
In lung cancer patients with early-stage disease, we collaborate closely with thoracic surgeons and radiation therapists to better optimize the different treatment approaches and modalities set within a truly multidisciplinary setting. Since lung cancer patients sometimes suffer from severe symptoms associated with the disease, we strive to ameliorate them by working closely with a number of professionals from other disciplines. In patients with advancedstage disease, personalized therapy is now the standard approach and our key objective is the early implementation of molecular determinants to better select treatment options tailored to individual patients. Immunotherapy strategies have a role in the lung cancer management treatment algorithm; a number of protocols using this strategy are now ongoing in our unit.
We actively contribute to VHIO’s efforts aimed at early clinical drug development, and also deal with other less common thoracic malignancies such as small-cell lung cancer, mesothelioma, thymoma, and neuroendocrine tumors.
Jänne PA; Yang JC; Kim DW; Planchard D;Ohe Y; Ramalingam SS; Ahn MJ; Kim SW; Su WC; Horn L; Haggstrom D; Felip E; Kim JH; Frewer P; Cantarini M; Brown KH; Dickinson PA; Ghiorghiu S; Ranson M. AZD9291 in EGFR Inhibitor-Resistant Non-Small-Cell Lung Cancer. N Engl J Med. 2015;372(18):1689-1699.
Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Göker E, Georgoulias V, Li W, Isla D, Guclu SZ, Morabito A, Min YJ, Ardizzoni A, Gadgeel SM, Wang B, Chand VK, Goss GD; LUX-Lung 8 Investigators. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897-907.
Thress KS, Paweletz CP, Felip E, Cho BC, Stetson D, Dougherty B, Lai Z, Markovets A, Vivancos A, Kuang Y, Ercan D, Matthews SE, Cantarini M, Barrett JC, Jänne PA, Oxnard GR. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21(6):560-562.
Felip E, Concha Á, de Castro J, Gómez-Roman J, Garrido P, Ramírez J, Isla D, Sanz J, Paz-Ares L, López-Ríos F. Biomarker testing in advanced non-small-cell lung cancer: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology. 2015. Clin Transl Oncol. 2015;17(2):103-112.