Programs

Cancer Genomics Group

Ana Vivancos
Principal Investigator
Biosketch
Principal Investigator Ana Vivancos Post-Doctoral Fellows Alberto González, Miriam Sansó Specialized Technicians Ginevra Caratú, Deborah G. Lo Giacco, Agatha Martín, Judit Matito, Miriam Navarro, Zighereda Ogbah, Laia Ramos Bioinformatician Francesco M. Mancuso Bioinformatics Technical Auxiliary Marina Gómez, Laura Muiños

Summary

VHIO’s Cancer Genomics Group serves as a Core Technology laboratory. We are also dedicated to translational research as well as novel genomic test development.

Our group provides cutting-edge applications in cancer genomics through state-of-the-art technologies and the development of novel, fully validated tests that are used in the clinical research setting (Prescreening Program). Our lab is equipped with an n-Counter (Nanostring) platform, two digital PCR platforms (BEAMing Sysmex and ddPCR, BIO-RAD) and three NextGen Sequencers; MiSeq, NextSeq and HiSeq2500, Illumina. We are also starting to work with Minion Oxford Nanopore technology.

VHIO’s Prescreening Program, is nucleated around the activity of two VHIO groups – Cancer Genomics and Molecular Oncology, led by Paolo Nuciforo, in collaboration with VHIO’s Elena Garralda (PI of our Early Clinical Drug Development Group), and Rodrigo Dienstmann (PI, Oncology Data Science – ODysSey Group), together with Susana Aguilar and Jenifer Gonzalez. Our Advanced Molecular Diagnostics Program - DIAMAV, is supported by the FERO Foundation.

We perform molecular profiling in over 1100 patients each year as potential candidates for enrollment in our Phase I clinical trials led by VHIO’s Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa”, directed by Elena Garralda.

Patients’ suitability for inclusion in any given clinical trial is assessed based on their respective genomic or pathologic profile. Our Group has developed and routinely implemented several tests for our Prescreening Program. Two are based on NGS: an Amplicon-seq approach to sequence 67 genes as well as a 450-gene capture panel (Illumina). We use nCounter (Nanostring) for our RNA-based gene fusion panel, with the capacity of detecting over 100 recurrent gene fusions (also enabling us to assess gene expression patterns in tumors), and our Copy Number Alterations panel, evaluating a 59 gene panel for genes with frequent gains or losses in cancer.

As a reflection of our dedication to excellence and quality in the services we provide, we have attained ISO 15189 flexible accreditation for our Amplicon-seq testing method and will soon obtain it for our large 450-gene capture panel.

Research activities focus on developing novel multiplexed tests that are optimized to FFPE-derived nucleic acids. Once developed, they are validated and used in both clinical and translational research.

We are also involved in a number of translational research projects including the identification of mechanisms of resistance to targeted therapies, as well as predictive biomarkers for immunotherapeutics. Our group is particularly interested in liquid biopsy and on RNA-based analysis of tumors for microenvironment profiling.


Genome-wide Copy Number Alteration (CNA) by shallow whole genome sequencing (shWGS) analysis of solid and liquid biopsies to follow residual disease and progression of a patient with lung adenocarcinoma. A. Samples collected from a patient with EGFR L858R mutated NSCLC depicted at the top of the plot, lines of treatments at the bottom of x axis, and results of liquid biopsy follow-up by ddPCR of a EGFR mutation panel. Mutant allelic fractions (MAF%) for L858R and T790M EGFR mutations (left y axis), cell free DNA concentration (right y axis) . B. Results from shWGS for the biopsy at diagnosis (upper panel), from the plasma collected at response to erlotinib (middle panel) and from the plasma collected at progression disease (bottom panel).

Strategic goals

  • Develop and implement improved strategies for routine patient prescreening with a large pan-cancer panel in a setting of excellence (ISO 15189 flexible accreditation).
  • Provide cutting-edge applications in cancer genomics through the use of novel technologies and protocol development.
  • Prioritize translational projects and partnerships that reinforce VHIO's renowned excellence in oncology.

Highlights

  • VHIO is one of the six founding partners of the Cancer Core Europe Consortium (CCE) alongside 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), and the National Center for Tumor Diseases–DKFZ-NCT (Heidelberg, Germany), and, most recently incorporating the National Cancer Institute of Milan (INT). Our group is appointed co-leader of the Consortium's Genomics Taskforce and is responsible for the alignment of genomic testing across all member institutions
  • We have validated our 450 gene capture panel for Tumor Mutational Burden and for Copy Number Alterations be used in our Prescreening Program.
  • In liquid biopsy, we are developing Copy Number Alteration analysis through the use of shallow Whole Genome Sequencing to provide data along with our custom NGS test with Unique Molecular Identifiers (UMI) chemistry and envision that this will be our first disease tracking test in the clinical setting.
  • Driven by our Advanced Molecular Diagnostics Program - DIAMAV, supported by the FERO Foundation, VHIO is one of the few centers in Europe to run such a comprehensive prescreening program. Molecular profiling in around 1100 patients per year as candidates for enrollment in our Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa” early clinical trials, enables our teams to more precisely match an increasing number of individual patients with a particular study.

Horizons

  • To implement improved strategies for routine patient Prescreening with a large pan-cancer panel in a setting of excellence (ISO 15189 flexible accreditation).
  • Provide cutting-edge applications in cancer genomics through the use of novel technologies and protocol development.
  • Prioritize translational projects and partnerships that reinforce VHIO's renowned excellence in oncology.

PI paper pick

  • Capdevila J, Mayor R, Mancuso FM, Iglesias C, Caratú G, Matos I, Zafón C, Hernando J, Petit A, Nuciforo P, Cameselle-Teijeiro JM, Álvarez CV, Recio JA, Tabernero J, Matias-Guiu X, Vivancos A, Seoane J. Early evolutionary divergence between papillary and anaplastic thyroid cancers. Ann Oncol. 2019 Nov 1;30(11):1843.
  • Elez E, Chianese C, Sanz-García E, Martinelli E, Noguerido A, Mancuso FM, Caratù G, Matito J, Grasselli J, Cardone C, Esposito Abate R, Martini G, Santos C, Macarulla T, Argilés G, Capdevila J, Garcia A, Mulet N, Maiello E, Normanno N, Jones F, Tabernero J, Ciardello F, Salazar R, Vivancos A. Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer. Mol Oncol. 2019 Sep;13(9):1827-1835.
  • Vivancos A, Aranda E, Benavides M, Élez E, Gómez-España MA, Toledano M, Alvarez M, Parrado MRC, García-Barberán V, Diaz-Rubio E. Comparison of the Clinical Sensitivity of the Idylla Platform and the OncoBEAM RAS CRC Assay for KRAS Mutation Detection in Liquid Biopsy Samples. Sci Rep. 2019 Jun 20;9(1):8976.
  • Rodriguez-Freixinos V, Ruiz-Pace F, Fariñas-Madrid L, Garrido-Castro AC, Villacampa G, Nuciforo P, Vivancos A, Dienstmann R, Oaknin A. Genomic heterogeneity and efficacy of PI3K pathway inhibitors in patients with gynaecological cancer. ESMO Open. 2019 Mar 8;4(2):e000444.

Full list of Publications

  1. Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer. Serna G, Ruiz-Pace F, Cecchi F, Fasani R, Jimenez J, Thyparambil S, Landolfi S, Elez E, Vivancos A, Hembrough T, Tabernero J, Dienstmann R, Nuciforo P. Sci Rep. 2019 Sep 19;9(1):13568.
  2. Early evolutionary divergence between papillary and anaplastic thyroid cancers. Capdevila J, Mayor R, Mancuso FM, Iglesias C, Caratú G, Matos I, Zafón C, Hernando J, Petit A, Nuciforo P, Cameselle-Teijeiro JM, Álvarez CV, Recio JA, Tabernero J, Matias-Guiu X, Vivancos A, Seoane J. Ann Oncol. 2019 Nov 1;30(11):1843.
  3. Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS-mutant metastatic colorectal cancer.Elez E, Chianese C, Sanz-García E, Martinelli E, Noguerido A, Mancuso FM, Caratù G, Matito J, Grasselli J, Cardone C, Esposito Abate R, Martini G, Santos C, Macarulla T, Argilés G, Capdevila J, Garcia A, Mulet N, Maiello E, Normanno N, Jones F, Tabernero J, Ciardello F, Salazar R, Vivancos A. Mol Oncol. 2019 Sep;13(9):1827-1835.
  4. Comparison of the Clinical Sensitivity of the Idylla Platform and the OncoBEAM RAS CRC Assay for KRAS Mutation Detection in Liquid Biopsy Samples. Vivancos A, Aranda E, Benavides M, Élez E, Gómez-España MA, Toledano M, Alvarez M, Parrado MRC, García-Barberán V, Diaz-Rubio E. Sci Rep. 2019 Jun 20;9(1):8976.
  5. Genomic heterogeneity and efficacy of PI3K pathway inhibitors in patients with gynaecological cancer. Rodriguez-Freixinos V, Ruiz-Pace F, Fariñas-Madrid L, Garrido-Castro AC, Villacampa G, Nuciforo P, Vivancos A, Dienstmann R, Oaknin A. ESMO Open. 2019 Mar 8;4(2):e000444.

Projects

  1. Avanzando hacia la implementación clínica: Estudio de las bases moleculares de la liberación de DNA tumoral en sangre. FIS-ISCIII.  (PI20/01112).
    PI: Ana Vivancos.
    01/01/2021 - 31/12/2023.
  2. Validation of BRCA1/2 mutation detection in Tissue and Germline. AstraZéneca.
    PI: Ana Vivancos.
    02/05/2020 - 31/12/2020.
  3. ctDNA in breast milk for early detection of pregnancy associated breast cancer. FERO.
    PI: Ana Vivancos.
    01/07/2020 - 30/06/2022.
  4. Tumores primarios múltiples en pacientes con cáncer de pulmón: elaboración de un perfil molecular integral para elucidar orígenes genéticos comunes.
    Fundación Científica de la Asociación Española Contra el Cáncer (AECC).
    PI: Ana Vivancos.
    01/12/2019 - 30/11/2023.
  5. Phase II Study of Avelumab plus chemotherapy in the peri-operative treatment for patients with resectable Gastric cancer (GC) or Gastroesophageal Junction cancer (GECJ).
    Merck Healthcare KGaA.
    PI: Ana Vivancos.
    10/04/2019 - 31/12/2026.
  6. Measuring NRG1 mRNA levels by means of Nanostring at Vall d'Hebron.
    MERUS, NV.
    PI: Ana Vivancos.
    30/04/2019 - 31/12/2020.
  7. Biomarker testing NSG analysis.
    Puma Biotechnology, Inc.
    PI:  Ana Vivancos.
    01/01/2019 - 30/09/2020
  8. CeLac and European consortium for a personalized medicine approach to Gastric Cancer-LEGACy.
    European Commission-LEGACy.
    PI: Ana Vivancos.
    01/01/2019-31/12/2022.

Molecular Oncology Group

Paolo Nuciforo
Principal Investigator
Biosketch
Principal Investigator Paolo Nuciforo Attending Physicians Roberta Fasani, Sara Simonetti Laboratory Supervisor Jose Antonio Jimenez Laboratory Assistant Mª Angeles Diaz Post-Doctoral Fellow Francisca Gallego PhD Student Garazi Serna Technicians Lidia Alonso, Clara Castan, Eloy Garcia, Xavier Guardia, Paola Martinez, Stefania Napoli, Gertrudis Sanchez, Lidia Sanchez, Cesar Javier Sevillano Students Audrey Detolle, Esther Farell, Kristiana Plamenova

Summary

The mission of VHIO’s Molecular Oncology Group 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 medicine in oncology.

Together with VHIO’s Cancer Genomics Group (PI Ana Vivancos), and Oncology Data Science - ODysSey Group (PI Rodrigo Dienstmann), along with Susana Aguilar and Jenifer Gonzalez, our group participates in VHIO’s Molecular Prescreening Program. We molecularly profile over 1100 patients per year as candidates for enrolment in early phase clinical trials at our Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa”). We also serve as one of VHIO’s Core Technology Platforms and our laboratory is therefore key to our translational research lines and programs.

We actively participate in all projects involving the use of human tissue collected from patients, including biomarker analyses for patient stratification and inclusion in clinical trials, digital pathology, tissue banking and the development of primary patient-derived xenograft (PDX) models. Our contribution is reflected by several high-impact factor collaborative papers published throughout 2019.

Our group also continues to work both independently as well as in partnership to establish the impact of microbiome in colorectal cancer development and progression. In particular, we are developing a Fusobacterium nucleatum diagnostic assay that permits the simultaneous visualization and quantification of bacteria within tumors.

As a Core Facility we have provided support for approximately 280 clinical studies conducted at Vall d’Hebron, representing around 70% of all currently open trials at our institution. Our involvement in clinical trials ranges from the coordination of sample collection, storage and shipment, developing and running multiple assays for real-time patient inclusion, as well as pharmacodynamic monitoring and dose finding.

In 2019 we performed more than 4000 molecular determinations on samples for patient inclusion in clinical trials, and over 23,000 tests to support basic and translation research. We have also served as the central laboratory of choice for 10 international studies, and successfully maintained the prestigious ISO15189 accreditation that endorses quality and competence.


Intratumoral bacteria visualization by in situ hybridization stainings using bacteria-specific RNA probes (virtual image reconstruction, green for Fusobacterium nucleatum and red for Propionibacterium acnes).

Strategic goals

  • Discovery and validation of novel biomarkers using tissue-based technologies.
  • Identification of targetable alterations as part of VHIO's Prescreening Program.
  • Application of molecular pathology strategies to support early clinical drug development programs.
  • Resolve spatial interaction of tumor-associated microbiota, tumor cells, and immune cells in the tumor microenvironment.
  • Better define molecular target epidemiology to render treatment strategies more precise.
  • Act as a central and local laboratory in clinical trials.
  • Serve as a Core Facility for VHIO research programs.

Highlights

  • Application of targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer (Scientific Reports 2019).
  • Work-package leader and central laboratory for the Horizon 2020-supported COLOSSUS - Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions.

Horizons

  • To significantly contribute to the field of cancer microbiome by interrogating the cancer-associated microbiome in the search for diagnostic, prognostic and/or predictive biomarkers in colorectal cancer as well as other tumor types.
  • Apply proteomics to precision medicine in oncology.
  • Explore the utility of Artificial Intelligence (AI) in pathology.

PI paper pick

  • Serna G, Ruiz-Pace F, Cecchi F, Fasani R, Jimenez J, Thyparambil S, Landolfi S, Elez E, Vivancos A, Hembrough T, Tabernero J, Dienstmann R, Nuciforo P. Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer. Sci Rep. 2019 Sep 19;9(1):13568.
  • Saura C, Hlauschek D, Oliveira M, Zardavas D, Jallitsch-Halper A, de la Peña L, Nuciforo P, Ballestrero A, Dubsky P, Lombard JM, Vuylsteke P, Castaneda CA, Colleoni M, Santos Borges G, Ciruelos E, Fornier M, Boer K, Bardia A, Wilson TR, Stout TJ, Hsu JY, Shi Y, Piccart M, Gnant M, Baselga J, de Azambuja E. Neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with oestrogen receptor-positive, HER2-negative, early-stage breast cancer (LORELEI): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2019 Sep;20(9):1226-1238. doi: 10.1016/S1470-2045(19)30334-1.
  • Oliveira M, Saura C, Nuciforo P, Calvo I, Andersen J, Passos-Coelho JL, Gil Gil M, Bermejo B, Patt DA, Ciruelos E, de la Peña L, Xu N, Wongchenko M, Shi Z, Singel SM, Isakoff SJ. FAIRLANE, a double-blind placebo-controlled randomized phase II trial of neoadjuvant ipatasertib plus paclitaxel for early triple-negative breast cancer. Ann Oncol. 2019 Aug 1;30(8):1289-1297.

Projects

  1. Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions (COLOSSUS, H2020).
  2. OPportunity To Investigate the Microbiomes’s Impact on Science and Treatment In Colorectal Cancer (OPTIMISTICC, Grand Challenge, Cancer Research UK).

Clinical Trials

We participate in the following studies as a Central Lab:

  • A phase II randomized, double-blind study of neoadjuvant letrozole plus GDC-0032 versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative, early breast cancer. Sponsor: GENETECH/SOLTI. Central Laboratory. From 2016.
  • A Study of Ipatasertib (GDC-0068) in Combination With Paclitaxel as Neoadjuvant Treatment for Patients With Early Stage Triple Negative Breast Cancer. Sponsor: GENETECH/SOLTI. Central Laboratory. From 2017.
  • A Phase I Study to Evaluate the Safety, Tolerability, and Efficacy of VCN-01in Combination  With Durvalumab  (MEDI4736)  in Subjects  With  Recurrent/ MetastaticSquamous Cell Carcinoma of the Head and Neck (ICO-VCN-H&N-2018)   ICO-VCN-H&N. Sponsor: VCN Biosciences. Central Laboratory. From 2018.
  • Phase I/Ib trial of single agent PBF-999 in solid tumour Advanced cancer (VHIO-PBF-999-01). Sponsor: Palobiofarma. Central Laboratory. From 2018.
  • A safety, tolerability and pharmacokinetic dose escalation and expansion, Phase I/Ib study of AMC303 as monotherapy in patients with advanced or metastatic, malignant solid tumour of epithelial origin (AMC303-01)
  • A phase I/IIA multi-centre, open-label, dose-escalation study with expansion arms to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of CB-103 administered orally in adult patients with advanced or metastatic solid tumours and haematological malignancies characterized by alterations of the notch signalling pathway (CB103-C-101).
  • A Phase Ib Study to Evaluate the Safety, Tolerability and Efficacy of Gatipotuzumab and Tomuzotuximab Combination in Patients with EGFR-Positive Metastatic Solid Tumors (5225101 GATTO).

Proteomics Group

Francesc Canals
Principal Investigator
Biosketch
Principal Investigator Francesc Canals Post-Doctoral Fellow Núria Colomé Technicians Luna Martín, Anna Sabé

Summary

VHIO’s Proteomics Group serves as a Core Technology Platform, provides state-of-the-art proteomic methodologies to VHIO researchers, and incorporates new developments within the field to offer the very latest strategies and technologies in the field.

We employ mass spectrometry-based proteomic strategies for the screening and validation of biomarkers for cancer diagnostics, precision therapy and the closer monitoring of disease.

One of our research lines focuses on the development of mass spectrometry-based assays for the analysis of biomarkers in clinical samples. We have been developing immune-MS based assays with improved selectivity and accuracy in the analysis of low abundance biomarker proteins in plasma or CSF samples.

Our group also develops MS based assays for marker proteins in FFPE tissue samples, aimed at providing accurate quantitative measurements that can translate in superior stratification compared with routine IHC scoring methods.

We have set up workflows for the proteomic and phosphoproteomic characterization of patient-derived xenograft (PDX) models of colorectal cancer. PDX constitute an ideal platform for the molecular characterization at the proteomic level of this tumor type. Complementary to genomic classification, we are exploring the suitability of this characterization as a tool for tumor subtype classification.

VHIO’s Proteomics Group is a member of the Spanish Consortium Chromosome 16 HPP which forms part of the HUPO Human Proteome Project. Following a chromosome-centric strategy, this multicenter and international project seeks to develop an entire map of the proteins encoded by the human genome to advance our understanding of human biology in health and disease.


Proteomics in preclinical and translational research. Our laboratory provides mass spectrometry based analysis of plasma, tissue or FFPE samples for: A) monitoring small drugs in plasma or tissue of model animals for pharmacokinetic characterization. B) Profiling of total proteome and phosphoproteome of PDX tumor models to explore pathways involved in therapeutic response. C) targeted LCMS analysis and D) immune-MS analysis, to measure levels of biomarkers in clinical samples for patient stratification or treatment monitoring.

Strategic goals

  • Provide services in proteomic techniques to other research groups as a Core Facility.
  • Proteomic screening for new biomarkers to help develop cancer therapeutics.
  • Development of mass spectrometry-based assays for the analysis of biomarkers in clinical samples.
  • Contribute to mapping the Chromosome 16 proteome as part of the Human Proteome Project.

Highlights

  • The provision of proteomic services to VHIO groups, oncology professionals at the Vall d'Hebron University Hospital (HUVH), and members of the ProteoRed-Instituto Salud Carlos III network.
  • Application of proteomic and phosphoproteomic screening to the characterization of CRC PDX models
  • Setting up mass spectrometry based analytical methods to monitor specific drugs in plasma and tumor tissue, to monitor preliminary pharmacokinetics in preclinical mouse models.
  • Participation in the Spanish Consortium Chromosome 16 HPP, the HUPO Human Proteome Project.

Horizons

  • Proteomic screening for novel biomarkers towards developing cancer therapeutics. Current projects are related to ADAM and ADAMTS metalloproteases in breast cancer, and the proteomic and phosphoproteomic screening of CRC PDX models.
  • Development of MS-based assays to monitor cancer biomarkers in clinical samples, particularly plasma and FFPE samples.
  • Continued involvement in the HUPO Human Proteome Project through the Spanish Chromosome 16 HPP Consortium.
  • Provide state-of-the art proteomic methodologies to other research groups.

PI paper pick

  • Arreal L, Piva M, Fernández S, Revandkar A, Schaub- Clerigué A, Villanueva J, Zabala-Letona A, Pujana M, Astobiza I, Cortazar AR, Hermanova I, Bozal-Basterra L, Arruabarrena-Aristorena A, Crespo JR, Valcarcel-Jimenez L, Zúñiga-García P, Canals F, Torrano V, Barrio R, Sutherland JD, Alimonti A, Martin-Martin N, Carracedo A. Targeting PML in triple negative breast cancer elicits growth suppression and senescence. Cell Death Differ. 2019 Oct 1.
  • Garcia-Puig A, Mosquera JL, Jiménez-Delgado S, García-Pastor C, Jorba I, Navajas D, Canals F, Raya A. Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration. Mol Cell Proteomics. 2019 Sep;18(9):1745-1755.
  • Marcelino I, Colomé-Calls N, Holzmuller P, Lisacek F, Reynaud Y, Canals F, Vachiéry N. Sweet and Sour Ehrlichia: Glycoproteomics and Phosphoproteomics Reveal New Players in Ehrlichia ruminantium Physiology and Pathogenesis. Front Microbiol. 2019 Mar 15;10:450.

Projects

  1. Plataforma de Recursos Biomoleculares (PRB3)
    Funding Agency: Instituto de Salud Carlos III (ISCIII)
    Reference: PT17/0019/0027
    2018 - 2020