VHIO's Cancer Genomics, Molecular Oncology, Proteomics, and Translational Genomics Groups led by Ana Vivancos, Paolo Nuciforo, Francesc Canals, and Aleix Prat respectively, are responsible for the development of VHIO's cutting-edge core technologies and platforms. These groups also pursue, implement, and develop their own independent research lines and projects.
Deborah G. Lo Giacco
Francesco M. Mancuso
Bioinformatics Technical Auxiliary
VHIO’s Cancer Genomics Group serves as a Core Technology laboratory. Our activities bridge the preclinical and clinical fields of cancer research. We provide cutting-edge applications in cancer genomics through the use of state-of-the-art technologies and also develop novel fully validated tests that are used in the clinical research setting (Pre-screening Program).
Our lab is equipped with a genotyping platform (MassARRAY, Sequenom), an n-Counter (Nanostring) platform and two NextGen Sequencers; MiSeq and HiSeq2500, Illumina.
Our research activities focus on developing novel multiplexed tests that are optimized to FFPE-derived nucleic acids. Once developed, our tests are validated and used in clinical research – VHIO’s Prescreening Program. We have developed and routinely implemented an Amplicon-seq approach to sequence >60 genes (Illumina), as well as a gene fusion panel (with the capacity of detecting over 100 recurrent gene fusions) based on nCounter technology.
VHIO’s Pre-screening Program is nucleated around the activity of two VHIO groups - our Cancer Genomics Group and Molecular Oncology led by Ana Vivancos and Paulo Nuciforo respectively, and is dedicated to performing molecular profiling in over 1500 patients per year that are candidates for enrollment in Phase I clinical trials carried out at our Research Unit for Molecular Therapy of Cancer (UITM) – “la Caixa”. Patients’ suitability for inclusion in a given clinical trial is decided upon based on their respective genomic or pathologic profile. As a reflection of our dedication to excellence and quality in the services we provide, we have undergone ISO 15189 accreditation for our main testing methods.
We are also involved in a number of translational research projects including the identification of mechanisms of resistance to targeted therapies, study of clonal populations, as well as defining novel therapeutic opportunities based on mutation profiles, in collaboration with both preclinical and clinical researchers at VHIO, working on solid tumors.
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.
Arqués O, Chicote I, Puig I, Tenbaum SP, Argilés G, Dienstmann R, Fernández N, Caratù G, Matito J, Silberschmidt D, Rodon J, Landolfi S, Prat A, Espín E, Charco R, Nuciforo P, Vivancos A, Shao W, Tabernero J, Palmer HG. Tankyrase Inhibition Blocks Wnt/b-Catenin Pathway and Reverts Resistance to PI3K and AKT Inhibitors in the Treatment of Colorectal Cancer. Clin Cancer Res. 2016;22(3):644-656. Epub 2015 Jul 29.
García-García C, Rivas MA, Ibrahim YH, Calvo MT, Gris-Oliver A, Rodríguez O, Grueso J, Antón P, Guzmán M, Aura C, Nuciforo P, Jessen K, Argilés G, Dienstmann R, Bertotti A, Trusolino L, Matito J, Vivancos A, Chicote I, Palmer HG, Tabernero J, Scaltriti M, Baselga J, Serra V. MEK plus PI3K/mTORC1/2 Therapeutic Efficacy Is Impacted by TP53 Mutation in Preclinical Models of Colorectal Cancer. Clin Cancer Res. 2015;21(24):5499-5510.
Mª Alejandra Gabaldón
Mª Ángeles Díaz
Mª del Carmen Díaz
Mª Alejandra Iglesias
The Molecular Oncology Group’s mission is to apply state-of-the-art tissue-based technologies to basic, translational, and clinical research with a clear focus on developing and validating novel tumor biomarkers for precision cancer medicine. The group is one of VHIO’s Core Technology Platforms and is therefore central to VHIO’s research activities. We actively participate in all research projects involving the use of human tissue collected from patients, including biomarker analyses for patient stratification, tissue banking, the development of primary xenograft models, and circulating tumor cells (CTC) analyses.
Core Facility activities in 2015:
We provided support to more than 180 clinical trials conducted at Vall d’Hebron, representing more tan 60% of all trials open at our institution. Our clinical trials activities range from the coordination of simple collection, storage and shipment, developing and running multiple assays for real-time patient inclusion, as well as pharmacodynamic monitoring and dose finding.
During this year, we have performed over 3000 molecular determinations on samples for patient inclusion in clinical trials and over 14,000 tests to support basic and translation research programs. We have also been the central laboratory for 2 national and 6 international studies.
In 2015, our laboratory successfully maintained and expanded the catalogue of molecular tests run under the prestigious ISO15189 quality accreditation.
Research activities in 2015:
We published two papers addressing the role of PI3K pathway activation as a mechanism of resistance in HER2-positive breast cancer (Nuciforo et al, Annals of Oncology 2015; Majewski et al, Journal of Clinical Oncology 2015).
In addition, we established and strengthened several key collaborations with pharmaceutical companies to carry out translational studies focused on the identification of predictive biomarkers of response to FGFR inhibitors, the definition of target populations for two antibody-drug conjugates projects and HER family proteins quantification in breast cancer using Selected Reaction Monitoring Mass Spectrometry (SRM-MS).
The latter study, conducted in collaboration with MGH and OncoplexDx/Nantomics, aimed to demonstrate the feasibility of using SRM-MS in clinical samples and highlighted the relevance of quantitative target measurement in predicting response to targeted therapies (Nuciforo et al, Breast Cancer Research 2015; Scaltriti et al, Clinical Cancer Research 2015).
Additional projects included a study exploring the prevalence of MET copy number variation, MET expression and MET related genomic alterations in solid tumors.
Nuciforo P, Thyparambil S, Aura C, Garrido-Castro A, Vilaro M, Peg V, Jimenez J, Vicario R, Cecchi F, Hoos W, Burrows J, Hembrough T, Ferreres JC, Perez-Garcia J, Arribas J, Cortes J, Scaltriti M. High HER2 protein levels correlate with increased survival in breast cancer patients treated with anti-HER2 therapy. Mol Oncol. 2016;10(1):138-147. Epub 2015 Sep 15.
Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, de Azambuja E, Eidtmann H, Ellis CE, Baselga J, Piccart-Gebhart MJ, Michiels S, Bradbury I, Sotiriou C, Loi S. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated With Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial. JAMA Oncol. 2015;1(4):448-454. Erratum in: JAMA Oncol. 2015;1(8):1172.
Nuciforo P, Radosevic-Robin N, Ng T, Scaltriti M. Quantification of HER family receptors in breast cancer. Breast Cancer Res. 2015;17:53.
Nuciforo PG, Aura C, Holmes E, Prudkin L, Jimenez J, Martinez P, Ameels H, de la Peña L, Ellis C, Eidtmann H, Piccart-Gebhart MJ, Scaltriti M, Baselga J. Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status. Ann Oncol. 2015;26(7):1494-1500.
Proteomics is directed to the characterization of the entire set of proteins - proteome -expressed by a particular cell or tissue under specific physiological or pathological conditions. The application of proteomic technologies to cancer research is a rapidly expanding field - not only for basic research but also for the discovery of diagnostic or disease-progression biomarkers.
We mainly focus on the application of proteomic techniques to the identification and characterization of substrates of metalloproteases involved in tumor progression. Metalloproteases of the ADAM and ADAMTS families are known to play a crucial role in the regulation of the tumor microenvironment by mediating the remodeling of the extracelular matrix and the cleavage of specific extracellular and membrane proteins. Knowledge surrounding the substrates of these proteases in the context of tumor cells is required in order to elucidate their role in tumor growth and metastasis as well as evaluate their potential use as therapeutic targets. Our group employs mass spectrometry-based proteomic strategies to search for new substrates of these proteases and analyze their involvement in tumor progression.
Our research also adopts proteomic techniques for the screening and validation of biomarkers for cancer diagnostics, personalized therapy and the tracking of disease. Our group’s focus has mainly centered on the establishment of a TGF beta activity-related protein signature, to be used for patient stratification and monitoring of glioma.
Our laboratory is a member of the Spanish Consortium Chromosome 16 HPP which forms part of the HUPO Human Proteome Project. This multicenter, international project aims to develop an entire map of the proteins encoded by the human genome following a chromosome-centric strategy to advance our understanding of human biology in health and disease. Focusing on important aspects of biology, this project is set to impact on ongoing disease-oriented research.
As a Core Facility, we also provide state-of-the-art proteomic methodologies to VHIO researchers as well as implement new developments within the field in order to provide the very latest proteomic strategies and technologies.
Aguilera Ó, González-Sancho JM, Zazo S, Rincón R, Fernández AF, Tapia O, Canals F, Morte B, Calvanese V, Orgaz JL, Niell N, Aguilar S, Freije JM, Graña O, Pisano DG, Borrero A, Martínez-Useros J, Jiménez B, Fraga MF, García-Foncillas J, López-Otín C, Lafarga M, Rojo F, Muñoz A. Nuclear DICKKOPF-1 as a biomarker of chemoresistance and poor clinical outcome in colorectal cancer. Oncotarget. 2015;6(8):5903-5917.
Iñaki Alvarez, Javier A. Collado, Roger Colobran, Montserrat Carrascal, M. Teresa Ciudad, Francesc Canals, Eddie A. James, William W. Kwok, Martina Gärtner, Bruno Kyewski, Ricardo Pujol-Borrell, Dolores Jaraquemada. Central T cell tolerance: Identification of tissue-restricted autoantigens in the thymus HLA-DR peptidome. J Autoimmun. 2015;60:12-19.
Vilà-Rico Marta, Colomé-Calls Núria, Martín-Castel Luna, Gay Marina, Azorín Sebastián, Vilaseca Marta, Planas Antoni, Canals Francesc. Quantitative analysis of post-translational modifications in human serum transthyretin associated with familial amyloidotic polyneuropathy by targeted LC-MS and intact protein MS. J Proteomics. 2015;127(Pt B):234-246.
Andrew J. Percy, Jessica Tamura-Wells, Juan Pablo Albar, Jesus M. Arizmendi, Francisco J. Blanco, Francesc Canals, Fernando Corrales, Gilberto Domont, Guadalupe Espadas, Concha Gill, Mark Molloy, Young-Ki Paik, Mark Raftery, Lekha Sleno, Justina C. Wolters, Jong Shin Yoo, Victor Zgoda, Carol E. Parker, and Christoph H. Borchers. Inter-laboratory Evaluation of Instrument Platforms and Workflows for Quantitative Accuracy and Reproducibility. EuPA Open Proteomics. 2015;8:6-15.
Clinical Research Technician
Specialist Physician in Breast Cancer (Collaboration)
María Jesús Vidal Losada
2015 has been another highly productive year for VHIO’s Translational Genomics Group. On the one hand, we have been the first in Europe to successfully implement a clinically applicable gene expression-based test, known as PAM50, in two prospective clinical trials in patients with metastatic breast cancer. In addition, we have analyzed >1.000 samples and have continued to provide scientific guidance and advice to several collaborators both at VHIO and overseas, leading to multiple publications in high-impact factor journals. Moreover, my lab has expanded its participation in the retrospective genomic analyses of tumor samples from several national and international clinical trials (e.g. PAMELA, GEICAM2012-09, NeoEribulin, EGF30008, EGF104900, LPT109096, CIBOMA/2004-01/GEICAM 2003-11 and CHER-LOB).
Our group has also led important advances regarding the clinical implications of breast cancer heterogeneity. In a first article, published in Clinical Cancer Research, we were the first to validate the PAM50 assay in core biopsies from primary and metastatic tumors and evidence that this approach can help predict response to chemotherapy. In a second paper, published in BMC Medicine, in one of the largest datasets reported to date with more than 900 patients with breast cancer, we showed that PAM50 intrinsic subtyping predicts response and survival following multiagent chemotherapy. These findings have led to the clinical implementation at our hospital of the PAM50 assay at diagnosis before any therapeutic strategy is established for breast cancer patients.
Finally, we have collaborated with several renowned investigators. In one study, published in Science Translational Medicine, we showed that during PI3K inhibition in patients with luminal breast cancer, the tumor becomes more estrogen-dependent (i.e. more Luminal A). These findings have led, in part, to the development of these agents in combination with endocrine therapy. In a second study, we identified a gene, called MAF, as being potentially responsible for the development of breast cancer bone metastasis.
Our group has participated in 15 articles providing scientific advice and/or performing gene expression analyses including 13 original research articles and 1 review article: 3 as first author, 1 as second, and 2 as last author. For 2015 our group’s Impact Factor totaled at 110.5 (average of 8 per publication).
Prat A, Galván P, Jimenez B, Buckingham W, Jeiranian HA, Schaper C, Vidal M, Álvarez M, Díaz S, Ellis C, Nuciforo P, Ferree S, Ribelles N, Adamo B, Ramón Y Cajal S, Peg V, Alba E. Prediction of Response to Neoadjuvant Chemotherapy Using Core Needle Biopsy Samples with the Prosigna Assay. Clin Cancer Res. 2016;22(3):560-566. Epub 2015 Jul 7.
Prat A, Fan C, Fernández A, Hoadley KA, Martinello R, Vidal M, Viladot M, Pineda E, Arance A, Muñoz M, Paré L, Cheang MC, Adamo B, Perou CM. Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med. 2015;13:303.
Vidal M, Peg V, Galván P, Tres A, Cortés J, Ramón y Cajal S, Rubio IT, Prat A. Gene expression-based classifications of fibroadenomas and phyllodes tumours of the breast. Mol Oncol. 2015;9(6):1081-1090.
Prat A, Pineda E, Adamo B, Galván P, Fernández A, Gaba L, Díez M, Viladot M, Arance A, Muñoz M. Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast. 2015;24 Suppl 2:S26-S35.