Update for the steering group of the project "Personalized Medcine: eligble or not?", aiming to define whether and how to implement pharmacogenetic screening by first line care practitioners.

1. Implementation of Personalized Medicine
Professor of Personalized Healthcare
Head Radboud Center for Proteomics, Glycomics
and Metabolomics
Coordinator Radboud Technology Centers
Head Biomarkers in Personalized Healthcare
Bijeenkomst begeleidingscommissie
“Personalized medicine: eligible or not?”
2 June 2015
Prof Alain van Gool

2. My mixed perspectives in personalized health(care)
8 years academia (NL, UK)
(molecular mechanisms of disease)
13 years pharma (EU, USA, Asia)
(biomarkers, Omics)
3,5 years med school (NL)
(personalized healthcare, Omics, biomarkers)
3,5 years applied research institute (NL, EU)
(biomarkers, personalized health, nutrition)
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
2 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

3. Consider individual differences in personalized medicine
3
3 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

4. Source: Chakma, Journal of Young Investigators, 16, 2009
Principle of Personalized/Precision/Targeted Medicine
4
4 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015
Molecular biomarkers as key drivers to select right patient for right drug
at right dose at right time

5. Subapproaches of Personalized Medicine
5
Prognosis & prediction
Dosing Source: Kumar, van Gool, RSC 2013
5 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

6. Subapproaches of Personalized Medicine
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Patient selection
Source: Kumar, van Gool, RSC 2013
6 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

7. Next Generation Sequencing
Good examples personalized medicine in Oncology:
• Cyp450, Her2/neu, BRCA, BRAF, EGFR, EML4/ALK, etc
• Issue with drug resistancy in several solid tumors
Also beyond the oncology field:
• Volker: Intestinal surgery → XIAP → Cord blood
• Beery twins: Cerebral palsy → SPR → Diet 5HTP
• Wartman: Leukemia → FLT3 → Sunitinib
• Gilbert: Healthy → BRCA → Mas/Ovarectomy
• Snyder: T2Diabetes → GCKR, KCNJ11 → Diet, exercise
• Lauerman: Scotoma, leg → JAK2 → Aspirin
• Bradfield: Healthy → CDH1 → Gastrectomy
7 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

8. Rational selection of best targets and biomarkers works
The 5R’s assessment:
• Right Target
• Right Tissue
• Right Safety
• Right Patients
• Right Commercial Potential
8 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

9. Adopt Personalized Medicine in pharma research
CarTarDis = Cardiovascular Target Discovery
Public-private partnership, 13 partners, 8 countries, project budget 8.0M Eur
Started 1 Oct 2013 for 4 years
Adopting AstraZeneca’s 5R strategy in drug target selection
(Coordinator)
CarTarDis

10. Companion Diagnostics in drug labels
Metabolism
Efficacy or
safety
Source: www.fda.gov (June 2013)
10 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015
= molecular biomarker that indicates the right patient for right drug at
right dose at right time

11. Exponential developments in biomarker technologies
• 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
11 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

12. Mass spectrometry
• Example: Glycoproteomics in plasma
• Detection of ~12.000 unique deconvoluted monoisotopic masses
per single analysis (> 50% are glycopeptides)
500
1000
1500
2000
m/z
5 10 15 20 25 30 35 40 Time [min]
Proof of principle study:
Monique van Scherpenzeel, Dirk Lefeber, Hans Wessels, Alain van Gool
Translational Metabolic Laboratory, Radboudumc, unpublished data
12 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

13. Example: Personalized Medicine in rare diseases
• 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 developed and 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
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13 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

14. Imaging
Slide courtesy of Profs Maroeska Rovers, Peter Friedl, Otto Boerman, Radboudumc
Example: Image-guided surgery:
• Use (auto)fluorescence to highlight tumor cells
• Specific removal of tumor tissue
• Extend to other imaging modalities in operation room (eg MRI)
14 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

15. 15 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

16. 16 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015
Optimal personalized / targeted / precision medicine

17. Biomarkers in Personalized Health(care)
an evolving role
• From only diagnosis
• To Translational Medicine
• To Personalized/Precision/Targeted Medicine
• To Personalized Health(care)
present
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17 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

18. Goal of Personalized Health(care)
18
Source: prof Jan Kremer
18 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

19. Personalized Health(care), more than pathways only
Source: Barabási 2007 NEJM 357; 4}
• People are different
• Different networks and influences
• Different risk factors
• Different preferences
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19 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

20. Personalized Health(care) in a systems view
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20 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

21. The route to Personalized Health(care)
21 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

22. Analogy: TOMTOM
GPS to a location
Utrecht
Amsterdam
Utrecht
Amsterdam
Route 1 Route 2
= Default Traffic jam near Utrecht Alternative route
22 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

23. Personalized Health(care) model
GPS to health
Risk
Health
Route 1 Route 2
= Default
First signs of
disease risk
Alternative route
Now
Risk
Health
Now
23 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

24. Personalized Health(care) model
Analogies:
• Technology enabled
• Personal choice to actively monitor or not
• Success through participation of user
• Commercial competition of tool builders to standard of market leader(s)
• Implementation as standard in society
P4 medicine: Participatory, Predictive, Preventive, Personalized
GPS to health
24 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

25. ‘New’ data
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25 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

28. But …
Knowledge and Innovation gap:
1. What to measure?
2. How much can it change?
3. What should be the follow-up for me?
28 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

29. Biomarker innovation gaps
Discovery Clinical
validation/confirmation
Diagnostic
test
Number of
biomarkers
Gap 1
Gap 2
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Gap 3
29 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

30. Biomarker innovation gaps: some numbers
30
5 biomarkers/
working day
1 biomarker/
1-3 years
1 biomarker/
3-10 years
?
Eg Biomarkers in time: Prostate cancer
May 2011: n= 2,231 biomarkers
Nov 2012: n= 6,562 biomarkers
Oct 2013: n= 8,358 biomarkers
Nov 2014: n= 10,350 biomarkers
Discovery Clinical
validation/confirmation
Diagnostic
test
Number of
biomarkers
Gap 1
Gap 2
Gap 3
30 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

31. Drive biomarker validation through consortia
Standardisation, harmonisation,
knowledge sharing needed in:
1. Assay development
2. Clinical validation
Example: Biomarker Development Center
Open
Innovation
Network !
Roadmap Molecular Diagnostics
PPP Grant 4.3M Euro
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32. Most important for biomarkers in Personalized Healthcare:
Focus on the end user: the patient
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32 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

33. Translation is key in Personalized Healthcare !
“I’m afraid you’re
suffering from an
increased IL-1β and
an aberrant miR843
expression”
Adapted from:
33
?
33 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

34. Translation is key in Personalized Healthcare !
34
Personal profile data
Knowledge
Understanding
Decision
Action

35. Translation is key in Personalized Healthcare !
Treatment options
Pro’sCon’s
Select personalized therapy
35 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015

36. Personalized dietary advice
YOU HAVE:
Variation in gene
FADS1
YOU NEED:
Increase omega-3 /
omega-6 ratio
Personal information Health management
program
Personalized advice
ADVICE:
Include fatty fish,
pacific oysters, oils,
seeds and vegetables
in your diet
Translation is key in Personalized Healthcare !
Source: Suzan Wopereis et al, TNO

37. Patient
Radboud
Personalized Healthcare
A significant impact
on healthcare
Molecule
Population
Personalized Healthcare @Radboudumc
37

38. Acknowledgements
Ron Wevers
Jolein Gloerich
Hans Wessels
Monique Scherpenzeel
Dirk Lefeber
Leo Kluijtmans
Lucien Engelen
Paul Smits
Maroeska Rovers
Nathalie Bovy
Bas Bloem
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
Jan van der Greef
Ben van Ommen
Suzan Wopereis
Bas Kremer
Lars Verschuren
Ivana Bobeldijk
Marjan van Erk
Carina de Jongh
Peter van Dijken
Robert Kleemann
and many others
38
And funders
CarTarDis
38 Alain van Gool, “Personalized Medicine: eligible or not?”, 2 June 2015