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Biomarkers in personalized healthcare,
a changing world
Health Valley Event 2014
13 March 2014
Nijmegen
Head Radboud Cente...
Mixed perspectives in personalized healthcare
8 years academia (NL, UK)
(molecular mechanisms of disease)
13 years pharma ...
Biomarkers in personalized healthcare,
a changing world
• From Personalized Medicine to Personalized Healthcare
• Disrupti...
Personalized diagnostics in early days
This urine wheel was published
in 1506 by Ullrich Pinder, in his
book Epiphanie Med...
Personalized Medicine
Right patient
with right drug
at right dose
at right time
for right outcome
Only part of the biomark...
Pharmaceutical Companion Diagnostics – some numbers
At present in pharmaceutical development:
40.000 clinical trials ongoi...
Companion Diagnostics
Metabolism
Efficacy or
safety
Source: www.fda.gov
{Kumar and van Gool, RSC, 2013}
Health Valley Even...
Clinical efficacy of Vemurafenib (PLX-4032, Zelboraf)
Key biomarkers:
Stratification: BRAFV600E mutation
Mechanism: P-ERK
...
Clinical effects of Vemurafenib
{Wagle et al, 2011, J Clin Oncol 29:3085}
Before Rx Vemurafenib, 15 weeks Vemurafenib, 23 ...
Tumor tissue heterogeneity
• BRAFV600D/E is driving mutation
• However, also no BRAFV600D/E
mutation found in regions of a...
‘Complicating’ factors in oncology therapy
Source: 11 Sept 2013 @de Volkskrant
• Biological clock
• Smoking
• Pharma-Nutri...
Changing world: Personalized Medicine@ USA
“The term "personalized medicine" is
often described as providing "the
right pa...
Changing world: Personalized Medicine@ EU
(ESF, 30 Nov 2012) (IMI2, 8 July 2013) (EC, draft Nov 2013)
Health Valley Event ...
Emerging: Personalized Healthcare in a systems view
Source: Barabási 2007 NEJM 357; 4}
• People are different
• Different ...
Personalized Healthcare in a systems view
Health Valley Event 2014
Nijmegen
13 March 2014
Alain van Gool
Personalized Healthcare in a systems view
Health Valley Event 2014
Nijmegen
13 March 2014
Alain van Gool
Patient participa...
Radboud Personalized Healthcare
Stratification by multilevel diagnosis
Exchange experiences in
care communities
+
Patient’...
System biology model for Personalized Health(care)
(a.k.a. Next Generation Life Sciences)
HomeostasisAllostasisDisease
Tim...
Example System-based Personalized Healthcare
{Chen et al, Cell 2012, 148: 1293}
Concept:
• Continuous monitoring (n=1)
• R...
The big current bottleneck in Next Generation Life Sciences:
(Big) data
Knowledge
Understanding
Decision
Action
Translatio...
Systems view on metabolic health and disease
Visceral
adiposity
LDL elevated
Glucose toxicity
Fatty liver
Gut
inflammation...
EC DG for Research and Innovation
Alain van Gool
Brussels, 11 Sept 2012
Relating tissue pharmacology – biomarker - therapy...
Translating knowledge to field labs
• Implementation-plan ‘personalized diagnosis of
(pre)diabetic and their lifestyle tre...
Pharma-Nutrition potential
Effect
Dose
Horizon2020 consortium, call PHC-13
Higher efficacy / less side effects
However …
The world is changing and doesn’t wait for
scientific rigor to catch up
Health Valley Event 2014
Nijmegen
13 Mar...
Next Generation Life Sciences in USA
Health Valley Event 2014
Nijmegen
13 March 2014
Alain van Gool
Singularity University’s FutureMed 2013 speakers
Exponential
technologies
Digital
medicine
Integrated
care
Artifical
intel...
Singularity University’s FutureMed 2013 conference
Health Valley Event 2014
Nijmegen
13 March 2014
Alain van Gool
Exponential progress
“The only constant is change,
and the rate of change is
increasing”
We are at the knee
of the exponen...
1. Imaging of every part of human body in high resolution
2. Smartphone as the most important pieve of clothing
3. Self-di...
Digital medicine
Health Valley Event 2014
Nijmegen
13 March 2014
Alain van Gool
Self-diagnosis
Health Valley Event 2014
Nijmegen
13 March 2014
Alain van Gool
The future is nearly there …
Personalized advice
Action
Selfmonitor
Cloud
Lifestyle
Nutrition
Pharma
Health Valley Event 2...
Big Data
Exponential health(care) technologies
• IBM Watson
• AI system on top of recorded medical data + connected to Big Data clo...
Health Valley Event 2014
Nijmegen
13 March 2014
Alain van Gool
3 days high speed innovation in one slide
• Buzzwords:
• Exponential technologies
• Disruptive innovation
• Progress and b...
However …
Knowledge and Innovation gap:
1. What to measure?
2. How much should it change?
3. What should be the follow-up ...
A problem in biomarker land
Imbalance between biomarker discovery and application.
• Gap 1: Strong focus on discovery of n...
Some numbers
Data obtained from Thomson Reuters Integrity Biomarker Module
(April 2013)
Alzheimer’s Disease
Chronic Obstru...
Reasons for biomarker innovation gap
• Not one integrated pipeline of biomarker R&D
• Publication pressure towards high im...
“It is simply no longer possible to believe much of the clinical
research that is published, or to rely on the judgment of...
Shared biomarker development through open innovation
Needed: open innovation network to join forces in:
1. Assay developme...
Biomarker Development Center (Netherlands)
STW perspectief grant
Biomarker Development Center
Public-private partnership 4...
Translational medicine @ Radboudumc
Health Valley Event 2014
Nijmegen
13 March 2014
Alain van Gool
Radboudumc Technology Centers
Genomics
Bioinformatics Preclinical
therapies
Flow
cytometry
Translational
neuroscience
Nove...
Example: cross-technology diagnostics development
• 12 families with liver disease and dilated cardiomyopathy (5-20 years)...
Personalized Healthcare
Ways forward:
• Patients included
• Participation + collaboration
• Selfmonitoring
• Personal prof...
Acknowledgements
Jan van der Greef
Ben van Ommen
Peter van Dijken
Bas Kremer
Marijana Radonjic
Thomas Kelder
Robert Kleema...
Year 1
Applying lessons learned across fields
e.g. System Biology @TNO
Year 2
Year 3
Health Valley Event 2014: Alain van Gool, Radboudumc
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Health Valley Event 2014: Alain van Gool, Radboudumc

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Presentatie van Alain van Gool (Radboudumc) op het Health Valley Event 2014 tijdens de sessie Personalised Medicine.

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  • Integrating metabolic parameters with psychological parameters. Diabetes is mainly viewed as a metabolic disease. It becomes increasingly apparent that psychological aspects play a crucial role.
  • Transcript of "Health Valley Event 2014: Alain van Gool, Radboudumc"

    1. 1. Biomarkers in personalized healthcare, a changing world Health Valley Event 2014 13 March 2014 Nijmegen Head Radboud Center for Proteomics, Glycomics and Metabolomics Coordinator Radboud Technology Centers Head Biomarkers in Personalized Healthcare Prof Alain van Gool
    2. 2. Mixed perspectives in personalized healthcare 8 years academia (NL, UK) (molecular mechanisms of disease) 13 years pharma (EU, USA, Asia) (biomarkers, Omics) 2.5 years applied research institute (NL, EU) (biomarkers, personalized health) 2.5 years med school (NL) (Omics, biomarkers, personalized healthcare) A person / citizen / family man (adventures in EU, USA, Asia) 1991-1996 1996-1998 2009-2012 1999-2007 2007-2009 2009-2011 2011-now 2011-now 2 Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    3. 3. Biomarkers in personalized healthcare, a changing world • From Personalized Medicine to Personalized Healthcare • Disruptive technologies • Need to accelerate the development of useful tools Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    4. 4. Personalized diagnostics in early days This urine wheel was published in 1506 by Ullrich Pinder, in his book Epiphanie Medicorum. The wheel describes the possible colors, smells and tastes of urine, and uses them to diagnose disease. Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool Source: wikipedia {Kumar and van Gool, RSC, 2013}
    5. 5. Personalized Medicine Right patient with right drug at right dose at right time for right outcome Only part of the biomarker use in pharmaceutical development. Driven by the need to develop better drugs that work optimal in a selection of patients, rather than work mediocre in a larger patient group. Often translated to: Co-develop (molecular) biomarkers as diagnostic companions of a drug. In changing world: biomarkers are diagnostic companions of a person. Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    6. 6. Pharmaceutical Companion Diagnostics – some numbers At present in pharmaceutical development: 40.000 clinical trials ongoing 16.000 trials in oncology 8.000 trials in oncology have a companion diagnostic (many genetic) At present on market: 113 Biomarker in drug label (2012; up from 69 in 2010 = +64%) 16 CDx testing needed (2012; up from 4 in 2010 = +400%) Costs of development: >1.000 MUSD per drug ~10 MUSD per diagnostic Source: www.fda.gov Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    7. 7. Companion Diagnostics Metabolism Efficacy or safety Source: www.fda.gov {Kumar and van Gool, RSC, 2013} Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    8. 8. Clinical efficacy of Vemurafenib (PLX-4032, Zelboraf) Key biomarkers: Stratification: BRAFV600E mutation Mechanism: P-ERK Cyclin-D1 Efficacy: Ki-67 18FDG-PET, CT Clinical endpoint: progression-free survival (%) {Source: Flaherty et al, NEJM 2010}{Source: Chapman et al, NEJM 2011} Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    9. 9. Clinical effects of Vemurafenib {Wagle et al, 2011, J Clin Oncol 29:3085} Before Rx Vemurafenib, 15 weeks Vemurafenib, 23 weeks • Strong initial effects vemurafenib • Emerging drug resistancy • Reccurence of aggressive tumors Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    10. 10. Tumor tissue heterogeneity • BRAFV600D/E is driving mutation • However, also no BRAFV600D/E mutation found in regions of a primary melanoma • Molecular heterogeneity in diseased tissue • Biomarker levels in tissue will vary • Biomarker levels in body fluids will vary • Major challenge for (companion) diagnostics {Source: Yancovitz, PLoS One 2012} Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    11. 11. ‘Complicating’ factors in oncology therapy Source: 11 Sept 2013 @de Volkskrant • Biological clock • Smoking • Pharma-Nutrition • Drug-drug interaction • Alternative medicine • Genetic factors • … Interview with Prof Ron Matthijssen, ErasmusMC, Rotterdam Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    12. 12. Changing world: Personalized Medicine@ USA “The term "personalized medicine" is often described as providing "the right patient with the right drug at the right dose at the right time." More broadly, "personalized medicine" may be thought of as the tailoring of medical treatment to the individual characteristics, needs, and preferences of a patient during all stages of care, including prevention, diagnosis, treatment, and follow-up.” (FDA, 1 nov 2013) Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    13. 13. Changing world: Personalized Medicine@ EU (ESF, 30 Nov 2012) (IMI2, 8 July 2013) (EC, draft Nov 2013) Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    14. 14. Emerging: Personalized Healthcare in a systems view Source: Barabási 2007 NEJM 357; 4} • People are different • Different networks and influences • Different risk factors Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    15. 15. Personalized Healthcare in a systems view Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    16. 16. Personalized Healthcare in a systems view Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool Patient participation and empowerment included !!
    17. 17. Radboud Personalized Healthcare Stratification by multilevel diagnosis Exchange experiences in care communities + Patient’s preference of treatment People are different Select personalized therapy Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    18. 18. System biology model for Personalized Health(care) (a.k.a. Next Generation Life Sciences) HomeostasisAllostasisDisease Time Disease Health Personalized Intervention of patients-like-me Big Data Risk profiles of persons-like-me Molecular Non-molecular Environment … Personal profile Selfmonitoring Adapted from Jan van der Greef (2013) Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    19. 19. Example System-based Personalized Healthcare {Chen et al, Cell 2012, 148: 1293} Concept: • Continuous monitoring (n=1) • Routine biomarkers to alert • Omics to explain • Early intervention Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    20. 20. The big current bottleneck in Next Generation Life Sciences: (Big) data Knowledge Understanding Decision Action Translation ! Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    21. 21. Systems view on metabolic health and disease Visceral adiposity LDL elevated Glucose toxicity Fatty liver Gut inflammation endothelial inflammation systemic Insulin resistance Systemic inflammation Hepatic IR Adipose IR Muscle metabolic inflexibility adipose inflammation Microvascular damage Myocardial infactions Heart failure Cardiac dysfunction Brain disorders Nephropathy Atherosclerosis β-cell failure High cholesterol High glucose Hypertension dyslipidemia ectopic lipid overload Hepatic inflammation Stroke IBD fibrosis Retinopathy Physical inactivity Caloric excess Chronic Stress Disruption circadian rhythm Parasympathetic tone Sympathetic arousal Worrying Hurrying Endorphins Gut activity Sweet & fat foods Sleep disturbance Inflammatory response Adrenalin Fear Challenge stress β-cell Pathology gluc Risk factor Heart rate Heart rate variability High cortisol α-amylase Lipids, alcohol, fructose Carnitine, choline Stannols, fibre Low glycemic index Epicathechins Anthocyanins Soy Quercetin, Se, Zn, … Metformin Vioxx Salicylate LXR agonist Fenofibrate Rosiglitazone Pioglitazone Sitagliptin Glibenclamide Atorvastatin Omega3-fatty acids Pharma Nutrition Lifestyle {Source: Ben van Ommen, TNO} therapy Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    22. 22. EC DG for Research and Innovation Alain van Gool Brussels, 11 Sept 2012 Relating tissue pharmacology – biomarker - therapy Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    23. 23. Translating knowledge to field labs • Implementation-plan ‘personalized diagnosis of (pre)diabetic and their lifestyle treatment in Dutch Health care’. • Use of OGTT as a stratification biomarker for subgroups of (pre)diabetic patients • Use diagnosis for a tailored lifestyle (and medical) treatment for these subgroups Being implemented in 1st line care regio Hillegom Alliance “Expedition Sustainable Care, starting with diabetes” Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    24. 24. Pharma-Nutrition potential Effect Dose Horizon2020 consortium, call PHC-13 Higher efficacy / less side effects
    25. 25. However … The world is changing and doesn’t wait for scientific rigor to catch up Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    26. 26. Next Generation Life Sciences in USA Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    27. 27. Singularity University’s FutureMed 2013 speakers Exponential technologies Digital medicine Integrated care Artifical intelligence Robotics Patients included Lifestyle Self quantification Global health WatsonArtifical intelligence Regenerative medicine 23andme Robotics and Jamie Heywood (Patientslikeme) Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    28. 28. Singularity University’s FutureMed 2013 conference Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    29. 29. Exponential progress “The only constant is change, and the rate of change is increasing” We are at the knee of the exponential curve of progress Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    30. 30. 1. Imaging of every part of human body in high resolution 2. Smartphone as the most important pieve of clothing 3. Self-diagnosis as a continous monitoring to quantified self 4. Artifical intelligence and robots 5. Digital medicine, Big Data and wisdom of the crowd 6. Our body as a lego box using 3D printing for spare parts 7. Our brain online using brainsensing headbands to transfer thoughts Exponential trends Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    31. 31. Digital medicine Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    32. 32. Self-diagnosis Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    33. 33. The future is nearly there … Personalized advice Action Selfmonitor Cloud Lifestyle Nutrition Pharma Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    34. 34. Big Data
    35. 35. Exponential health(care) technologies • IBM Watson • AI system on top of recorded medical data + connected to Big Data clouds • Independent data-driven clinical diagnosis with very high accuracy • Artifical intelligence Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    36. 36. Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    37. 37. 3 days high speed innovation in one slide • Buzzwords: • Exponential technologies • Disruptive innovation • Progress and beyond • Digital quantified self • Focus on: • Where will we be in 5-20 years? • Technologies, genomics, robotics, Big Data, eHealth, patient empowerment • Less focus on: • What to do next year? • Biomarkers, robustness assays for decision, translating data to knowledge, innovation in clinical drug testing Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    38. 38. However … Knowledge and Innovation gap: 1. What to measure? 2. How much should it change? 3. What should be the follow-up for me? Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    39. 39. A problem in biomarker land Imbalance between biomarker discovery and application. • Gap 1: Strong focus on discovery of new biomarkers, few biomarkers progress beyond initial publication to multi-center clinical validation. • Gap 2: Insufficient demonstrated added value of new clinical biomarker and limited development of a commercially viable diagnostic biomarker test. Discovery Clinical validation/confirmation Diagnostic test Number of biomarkers Gap 1 Gap 2 The innovation gap in biomarker research & development Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    40. 40. Some numbers Data obtained from Thomson Reuters Integrity Biomarker Module (April 2013) Alzheimer’s Disease Chronic Obstructive Pulmonary Disease Type II Diabetes Mellitis Eg Biomarkers in time: Prostate cancer May 2011: 2,231 biomarkers Nov 2012: 6,562 biomarkers Oct 2013: 8,358 biomarkers 24 Feb 2014: 9,240 biomarkers with 28,538 biomarker uses EU: CE marking USA: LDT, 510(k), PMA Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    41. 41. 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 • Bias towards extreme results • Biomarker variability • … {Source: John Ioannidis, JAMA 2011} {Source: Khusru Asadullah, Nat Rev Drug Disc 2011} Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    42. 42. “It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgment of trusted physicians or authoritative medical guidelines. I take no pleasure in this conclusion, which I reached slowly and reluctantly over my two decades as an editor of The New England Journal of Medicine.” Marcia Angell, MD Former Editor-in-Chief NEJM Oct 2010 Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    43. 43. Shared biomarker development through open innovation Needed: open innovation network to join forces in: 1. Assay development of (diagnostic) biomarkers 2. Clinical biomarker quantification/validation/confirmation Shared knowledge, technologies and objectives through public-private partnerships (national, European, world-wide) Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    44. 44. Biomarker Development Center (Netherlands) STW perspectief grant Biomarker Development Center Public-private partnership 4 years Project grant 4.3M Eur of which 2.2M government, and 2.1M industry (0.9M cash/1.2M kind) Close interactions with: - Clinicians (biomarker application) - Industry - Patient stakeholder associations Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    45. 45. Translational medicine @ Radboudumc Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    46. 46. Radboudumc Technology Centers Genomics Bioinformatics Preclinical therapies Flow cytometry Translational neuroscience Novel concepts in surgery Imaging Microscopy Biobank Data stewardship Proteomics Glycomics Metabolomics Radboudumc Technology Centers GMP products Clinical trials (February 2014) Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    47. 47. Example: cross-technology diagnostics development • 12 families with liver disease and dilated cardiomyopathy (5-20 years) • Initial clinical assessment didn’t yield clear cause of symptoms • Specific sugar loss of serum transferrin identified via glycoproteomics ChipCube-LC- Q-tof MS • Outcome 1: Explanation of disease • Outcome 2: Dietary intervention as succesful personalized therapy • Outcome 3: Glycoprofile transferrin applied as diagnostic test • Genetic defect in glycosylation enzyme (PGM1) identified via exome sequencing {Tegtmeyer et al, NEJM 370;6: 533 (2014)} Genomics Glycomics Metabolomics Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    48. 48. Personalized Healthcare Ways forward: • Patients included • Participation + collaboration • Selfmonitoring • Personal profiles • System biology • (Big) Data sharing • Personal preferences • Personalized therapies • Lifestyle + Nutrition + Pharma Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    49. 49. Acknowledgements Jan van der Greef Ben van Ommen Peter van Dijken Bas Kremer Marijana Radonjic Thomas Kelder Robert Kleemann Suzan Wopereis Ton Rullmann Lars Verschuren William van Dongen and others Andrea Evers Lucien Engelen Jan Kremer Paul Smits Maroeska Rovers Nathalie Bovy Ron Wevers Jolein Gloerich Hans Wessels Dirk Lefeber Leo Kluijtmans and others Lutgarde Buydens Jasper Engel Jeroen Jansen Geert Postma and others Members of the Radboud umc Personalized Healthcare Taskforce (2013) Radboud umc Technology Centers (2014) alain.vangool@tno.nl alain.vangool@radboudumc.nl www.linkedIn.com Many external collaborators Health Valley Event 2014 Nijmegen 13 March 2014 Alain van Gool
    50. 50. Year 1 Applying lessons learned across fields e.g. System Biology @TNO Year 2 Year 3

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