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2016 09-12 Europe Biobanking Week, Vienna, Alain van Gool

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Opening keynote of the Europe Biobanking Week, outlining reasons why we should join forces in validation and development of biomarker in personalized medicinand health.

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2016 09-12 Europe Biobanking Week, Vienna, Alain van Gool

  1. 1. Biomarkers in Personalized Health(care): time for quality, not quantity Prof Alain van Gool
  2. 2. A short story: Personalized medicine in melanoma B-RAFV600E mutation Strong growth of cell Growth of tumor • B-RAFV600E cells always grow and become cancer cells • RAF inhibitors will block pathway, block cell growth and inhibit cancers that have a B-RAFV600E mutation • 60% of melanoma patients have B-RAFV600E mutation • Basis for a personalized medicine ! 2 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016 *
  3. 3. Biomarkers to support clinical development • Within Schering-Plough 4 Lead Optimisation programs in ERK pathway (2009) • Need for blood-based biomarker that indicated downstream effects of drugs: • Inhibition ERK pathway (pharmacodynamic) • Tumor inhibition (efficacy) • Extensive transcriptomics profiling: IL-8 as promising candidate biomarker Data for RAFi #4 RAFi MEKi ERKi RAFi#1 RAFi#2 RAFi#3 RAFi#4 MEKi#1 MEKi#2 ERKi#1 3 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  4. 4. Validation study to confirm IL-8 in melanoma Literature {Yurkovetsky, et al. Clin Cancer Res, 2007} Objectives: • Confirm elevated IL-8 in melanoma • Develop IL-8 assays for clinical use 4 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  5. 5. Validation study to confirm IL-8 in melanoma Stage 1 Stage 2 Stage 3 Stage 4 H&E staining; 20x 59 melanoma samples (tumor tissue (ffpe) + matching serum & plasma, stage I-IV, from two independent biobanks) + 40 healthy serum & plasma samples 1. Genetic analysis for BRAFV600E/D mutation in genomic DNA from tissue samples 2. IL-8 mRNA analysis in tissue samples by in situ hybridisation using bDNA probes (multiplexing with 12 ERK pathway response transcripts) 3. IL-8 protein analysis in tissue samples by immunohistochemistry (in parallel with 4 other ERK pathway response proteins, Ki67, Tunnel) 4. IL-8 protein analysis in matching plasma and serum by IL-8 immunoassay (3 formats: ELISA, Luminex, Mesoscale; singleplex and multiplex) partial OK OK ? 5 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  6. 6. Validation study to confirm IL-8 in melanoma Literature {Yurkovetsky, et al. Clin Cancer Res, 2007} Own data {Unpublished, 2010} Cause? (6 months, 4 fte, USD 1.000.000) 6 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  7. 7. Lessons learned? Source: Youtube - Burn after reading ending} 7 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  8. 8. Lessons learned? Particularly for this case: 1. Know sample history • IL-8 protein appeared sensitive to freeze-thawing 2. Know all relevant information from the source (patient) • Tumor load may be too low for our patients 3. Do these type of expensive validation studies together ! • For most pharma, biomarkers are precompetitive tools We need a biomarker community that shares knowledge, ambitions, capabilities, successes, failures and best practice. 8 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  9. 9. Alain’s path 1989-now • Molecular biology • Mechanisms of disease • Biomarkers • Omics / technologies • Translational medicine • Personalized healthcare Senior Scientist Integrator Biomarkers Scientific lead DTL-Technologies Head EATRIS Biomarker Platform Professor of Personalized Healthcare Head Radboud Center for Proteomics, Glycomics & Metabolomics Coordinator Radboud Technology Centers 9 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  10. 10. Consider individual differences in life science research 10 10 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  11. 11. Source: Chakma, Journal of Young Investigators, 16, 2009 Principle of Personalized Medicine 11 • The right drug for right patient at right dose at right time • Molecular biomarkers as key drivers of patient selection • = Precision medicine or Targeted medicine 11 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  12. 12. Personalized medicine in melanoma Treat patients with B-RAFV600E mutation Inhibit growth of cell Patients live longerTumors disappearCells stop growing B-RAFinhibitor 12 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  13. 13. Emerging Personalized / Precision / Targeted Medicine 2010: 5%of drugs in pipeline had companion diagnostic biomarker test 2015: 80% 50% 13 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  14. 14. 14 Optimal Personalized / Precision / Targeted Medicine
  15. 15. Moving to personalized health(care) {Source: Barabási 2007 NEJM 357; 4} • People are more than linear pathways • Different systems and networks • Different risk factors • Different preferences 15 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  16. 16. Societal need in efficient personalized health(care) {Source: prof Jan Kremer} Towards cost effective care, less cure 16 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  17. 17. Highest need in efficient personalized health(care) It’s personal ! ‘I want to stay healthy.’ ‘If not, how do I get healthy?’ 17 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  18. 18. 18 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016 Translating Personalized Health(care) in society
  19. 19. We need a personalized data-driven GPS for health • Monitor on background • Alert when you are at risk • Advice what to do 19 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  20. 20. 3 key aspects of personalized health(care) ‘I want to stay healthy. If not, how do I get healthy?’ 1. What to measure? 2. How much can it change? 3. What should be the follow-up for me? 20 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  21. 21. Exponential technological developments • Next generation sequencing • DNA, RNA • Risk analysis and therapy selection • Mass spectrometry • Proteins, metabolites • Monitoring of disease and treatment effects • Imaging • Non invasive images, real time • Spatial view of intact organs and organisms 500 1000 1500 2000 m/z 5 10 15 20 25 30 35 40 Time [min] 21 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  22. 22. Output from a proteomics biomarker lab • Mass spectrometry analysis of glycoproteins in human plasma • 0,05 microliter analysis: detection of 1.000.000 signals in one scan • ~40.000 peptides of which >80% contain sugar modification • Diagnose patients and identify new biomarkers 500 1000 1500 2000 m/z 5 10 15 20 25 30 35 40 Time [min] Proof of principle study: {Translational Metabolic Laboratory, Radboudumc, unpublished data} 22 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  23. 23. Challenge: translate laboratory to society • Heart beat • Steps / movement • Glasses water/coffee• 1.000.000 molecules per analysis 23 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  24. 24. 24 ‘Self’ data (generated by patients, citizens) 24 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  25. 25. What does my DNA tell me? 23% chance blond hair 3.1% Neanderthaler DNA 25 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  26. 26. Genetic risk lung cancer → don’t smoke ! What does my DNA tell me? No expected adverse reaction to Warfarin 26 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  27. 27. … but not all data is useful data !
  28. 28. Need for optimal quality in health biomarker analyses Test, interpret, advice “Post-traumatic Test Syndrome” ? 29 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  29. 29. 3 key aspects of personalized health(care) ‘I want to stay healthy. If not, how do I get healthy?’ 1. What to measure? 2. How much can it change? 3. What should be the follow-up for me? 30 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  30. 30. healthy disease disease + treatment 2. How much can it change? Subgroups 100% Individual Population Past Present Future 31 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  31. 31. 3 key aspects of personalized health(care) ‘I want to stay healthy. If not, how do I get healthy?’ 1. What to measure? 2. How much can it change? 3. What should be the follow-up for me? 32 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  32. 32. 3. What should be the follow-up for me? Personal profile data Knowledge Understanding (Shared) Decision Action 33 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  33. 33. 34 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  34. 34. Biomarker innovation gaps ! Discovery Clinical validation/confirmation Diagnostic test Number of biomarkers Gap 1 Gap 2 Gap 3 • Too much biomarker discovery • Too little development to application 35 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  35. 35. Biomarker innovation gaps: some numbers 5 biomarkers/ working day 1 biomarker/ 1-3 years 1 biomarker/ 3-10 years ? Eg Biomarkers in time: Prostate cancer May 2011: 2,231 biomarkers Nov 2012: 6,562 biomarkers Oct 2013: 8,358 biomarkers Nov 2014: 10,350 biomarkers Oct 2015: 11,856 biomarkers 12 Sept 2016: 13,888 biomarkers Discovery Clinical validation/confirmation Diagnostic test Number of biomarkers Gap 1 Gap 2 Gap 3 36 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  36. 36. Reasons for biomarker innovation gap • Not one integrated pipeline of biomarker R&D • Publication pressure towards high impact papers • Lack of interest and funding for confirmatory biomarker studies • Hard to organize multi-lab studies • Biology is complex on organism level • Data cannot be reproduced • Publishing bias towards extreme results • Biomarker variability • … {Source: John Ioannidis, JAMA 2011} {Source: Prinz, Schlange, Asadullah, Nat Rev Drug Disc 2011} Slide from: Alain van Gool, Eur Commission advice, 11 Sept 2012 37 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  37. 37. Irreproducibility of data {Freedman et al, PLOS Biology, 2015} {2012} {2011} {2013} {2008}{2012} 38 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  38. 38. Categories of errors leading to irreproducibility {Freedman et al, PLOS Biology, 2015} 39 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  39. 39. Add to this: bad Data Stewardship {Wilkinson et al, Nature Scientific Data, 2016} >80% of data is not FAIR: Findable, Accessible, Interoperable, Reusable 40 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  40. 40. Way forward Quote Freedman paper: {Freedman et al, PLOS Biology, 2015} 41 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  41. 41. Research Biomarkers Diagnostics Department of Laboratory Medicine Integrated Translational Research and Diagnostic Laboratory, 250 fte, yearly budget ~ 28M euro. Close interaction with Dept of Genetics, Pathology, Pharmacy and Medical Microbiology Specialities: • Proteomics, glycomics, metabolomics • Enzymatic assays • Neurochemistry • Cellulair immunotherapy • Immunomonitoring Areas of disease: • Metabolic diseases • Mitochondrial diseases • Lysosomal /glycosylation disorders • Neuroscience • Nefrology • Iron metabolism • Pediatric oncology • Immunodeficiency • Transplantation In development: • ~500 Biomarkers • Early and late stage • Analytical development • Clinical validation Assay formats: • Immunoassay • Turbidicity assays • Flow cytometry • DNA sequencing • Mass spectrometry • Experimental human (-ized) invitro and invivo models for inflammation and immunosuppression Validated assays*: • ~ 1000 assays • 3.000.000 tests/year Areas of application: • Personalized healthcare • Diagnosis • Prognosis • Mechanism of disease • Mechanism of drug action Departmental community *CCKL accreditation/RvA/EFI 42 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  42. 42. www.radboudumc.nl/research/technologycenters 43 Genomics Bioinformatics Animal studies Stem cells Translational neuroscience Image-guided treatment Imaging Microscopy Biobank Health economics Mass Spectrometry Radboudumc Technology Centers Investigational products Clinical studies EHR data analysis Statistics Human performance Data stewardship Molecule Flow cytometry 3D lab Institutional community
  43. 43. National communities Funding of Large scale Scientific Infrastructures (>10M euro) Data4LifeSciences (organising biomedical data in academic hospitals) National Technology Infrastructure (from 40+ partners in DTL) National Science Agenda (originated from citizens) 44 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  44. 44. Emerging Health Research Infrastructure in Netherlands 45 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  45. 45. 46 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  46. 46. 13-9-2016 47
  47. 47. European communities @Radboudumc: Peggy Manders Gerhard Zielhuis @Radboudumc: Peter Friedl Otto Boerman @Radboudumc: Otto Boerman (Head Imaging Platform) Alain van Gool (Head Biomarker Platform) @Radboudumc: Arnoud van der Maas Alain van Gool @Radboudumc: Saskia de Wildt Paul Smits 48 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  48. 48. Ongoing independent biomarker activities Europe USA {Asadullah et al, Nature Reviews Drug Discovery, Dec 2015} 49 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  49. 49. The Good Biomarker Practice initiative Join forces among Europe’s major academic infrastructures + industry to: 1. Establish “Good Biomarker Practice” guidelines - on translational research, biomarker technologies, biobanking, data stewardship. 2. Efficiently execute high quality biomarker projects - work together in clinical validation and development of probable biomarkers. 50 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016
  50. 50. Acknowledgements Hans Wessels Jolein Gloerich Roel Tans Esther Willems Maurice van Dael Jenneke Keizer Dirk Lefeber Monique van Scherpenzeel Leo Kluijtmans Ron Wevers Marcel Verbeek Lucien Engelen Jan Kremer Bas Bloem Nathalie Bovy Paul Smits the Radboudumc Technology Centers and many others www.radboudumc.nl/personalizedhealthcare www.radboudumc.nl/research/technologycenters www.radboudresearchfacilities.nl alain.vangool@tno.nl alain.vangool@radboudumc.nl www.linkedIn.com www.slideshare.net/alainvangool Many collaborators and funders Jan van der Greef Ben van Ommen Ivana Bobeldijk Hans Princen Lars Verschuren Marjan van Erk Suzan Wopereis Heleen Wortelboer Wessel Kraaij Ronald Mooi Peter van Dijken Cyrille Krul and many others CarTarDis Ruben Kok Barend Mons Jaap Heringa Merlijn van Rijswijk and many others Anton Ussi Florence Bietrix Laura Bermejo Andreas Scherer Sulev Koks Marian Hajduch Giovanni Migliaccio and many others 51 Alain van Gool, European Biobanking Week, Vienna, 12 Sept 2016

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