2016 03-02 rotary oss, alain van gool

Personalized Health(care): more than ‘just’ targeted medicines

Professor of Personalized Healthcare Head Radboud Center for Proteomics, Glycomics and Metabolomics Coordinator Radboud Technology Centers

Senior Scientist Integrator Biomarkers

Prof Alain van Gool

Rotary Oss 3 March 2016

Scientific lead DTL-Technologies Head Biomarker Platform

My background in personalized health(care)

8 years academia (NL, UK)

(molecular mechanisms of disease)

13 years pharma (EU, USA, Asia)

(biomarkers, Omics)

4 years med school (NL)

(personalized healthcare, Omics, biomarkers)

4 years applied research institute (NL, EU)

(biomarkers, personalized health, nutrition)

1991-1996 (PhD)

1996-1998 (post-doc)

2009-2012 (visiting prof)

1999-2007 2007-2009 2009-2011

2011-now

2011-now (prof)

2

A person / citizen / family man (adventures in EU, USA, Asia)

Alain van Gool, Rotary Oss, 3 Mar 2016

2016 (Scientific lead DTL-Technologies)

2016 (Head Biomarker Platform)

3 Alain van Gool, Rotary Oss, 3 Mar 2016

Consider individual differences in life science research

4


Source: Chakma, Journal of Young Investigators, 16, 2009

Principle of Personalized Medicine

5

• 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


Crash course in molecular biology

6

DNA, protein, cell, tissue, system biology


Biomarkers

{Biomarkers definition working group, 2001 }

Definition: ‘a characteristic that is objectively measured and evaluated as

an indicator of normal biological processes, pathogenic processes, or

pharmacologic responses to a therapeutic intervention’

Or ‘Whatever works in adding value’

Molecular biomarkers provide a molecular impression of a biological system

(cell, animal, human)

Biomarkers can be various sorts of data, or combinations thereof

Dutch CC meeting ‘Personalized Health Care”

Ede, 2 October 2013

Alain van Gool

Lecture LKCH, UMC Utrecht

29 October 2013

Alain van Gool


http://www.google.com/imgres?imgurl=http://upload.wikimedia.org/wikipedia/en/thumb/4/49/Cholesterol_structure.png/800px-Cholesterol_structure.png&imgrefurl=http://picsdigger.com/image/9bbfe1e8/&usg=__lgIeM7XqXX386731BUQz3NedgF8=&h=359&w=800&sz=24&hl=en&start=4&sig2=Zx35nHL-T3JMZ-sJMEym5A&um=1&itbs=1&tbnid=gcQNbxseIbu3DM:&tbnh=64&tbnw=143&prev=/images?q=cholesterol+structure&um=1&hl=en&tbs=isch:1&ei=PPYRTPbEFsKvrAea0dW3BA

http://www.google.com/imgres?imgurl=http://www.mc.uky.edu/Structuralbiology/psa_for_jack.jpg&imgrefurl=http://www.mc.uky.edu/Structuralbiology/&usg=__YXLZwCJp85cTWQYJzer1AzfgMHE=&h=535&w=750&sz=234&hl=en&start=1&sig2=AqVXjE_3CNeBw04PJ2IlZA&um=1&itbs=1&tbnid=tVXfc3lHcX1jHM:&tbnh=101&tbnw=141&prev=/images?q=psa+structure&um=1&hl=en&tbs=isch:1&ei=UPYRTPSiNcK-rAee6Mm0BA

http://www.google.com/imgres?imgurl=http://levis.tongji.edu.cn/gzli/image/t1-mri-brain-glioma.jpg&imgrefurl=http://levis.tongji.edu.cn/gzli/direction.htm&usg=__I1zN5qHq6Dy-XeIoV7PEErv_U50=&h=512&w=512&sz=59&hl=en&start=15&sig2=bkDWF22aiEMBpA-IuA0aZw&um=1&itbs=1&tbnid=rzCYX-mOOCfnxM:&tbnh=131&tbnw=131&prev=/images?q=mri+brain+tumor&um=1&hl=en&tbs=isch:1&ei=vfYRTPqYBorCrAfJ2bDDBA

Example: B-RAF mutations and melanoma

{Miller and Mihm,

2006}


Mechanism of pathophysiology in BRAF mutated tumors

• B-RAFV600E mutation: cell is always growing and becomes a cancer cell

• RAF inhibitors will block pathway, block cell growth and inhibit cancers that have a B-RAFV600E mutation

• Prevalence of B-RAFV600E is base for patient selection:

• Melanoma (60%), colon (15%), ovarian (30%), thyroid (30%) cancer

V600E

Kinase domain

{Roberts and Der, 2007}


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}


Vemurafenib trials

108 clinical studies


Emerging Personalized / Precision / Targeted Medicine

2010:

5% of drugs in pipeline had companion diagnostic biomarker test

2015:

80%

50%



Optimal Personalized / Precision / Targeted Medicine

People are more than linear pathways

Moving to Personalized Health(care)

“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, October 2013)

15


Societal need in efficient personalized health(care)

{Source: prof Jan Kremer}

Towards cost effective care, less cure


Personal need in efficient personalized health(care)

It’s personal !

‘I want to stay healthy.’ ‘If not, how do I get healthy?’


My route to Personalized Health(care)


Analogy: TOMTOM

GPS to a location

Amsterdam

Traffic jam

Amsterdam

Route 1 Route 2

= Default Traffic jam near Utrecht Alternative route


Personalized Health(care) model

GPS to health

Health

Route 1 Route 2

= Default First signs of disease risk

Alternative route

Now

Disease risk

Health

Now

Health


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?


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]


News from a molecular biomarker lab • Mass spectrometry analysis of glycoproteins in human plasma • 1 microliter analysis: detection of 100K features 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}


25

New data (generators, owners)


26


Demo room


28

Personalized advice

Action

Selfmonitor Cloud

Lifestyle Nutrition Pharma

DIY monitoring of vital signs


29

• Measure your brain waves (EEG)

• Recognize conditions for maximal concentration or relaxation.

• Use device to train.

DIY brainwave monitoring


DIY blood biomarker analysis

• Measure key biomarkers in one drop of blood at few $ per test panel

• Download data to your smartphone to monitor your own trend


• DIY sequence your genome and/or your microbiome genome • at a provider, at a pharmacy, at home

• Take your genome to the doctor • Have a personalized healthcare advice

DIY sequencing


23% chance blond hair

DIY sequencing

3.1% Neanderthaler DNA


Genetic risk lung cancer → don’t smoke !

DIY sequencing

No expected adverse reaction to Warfarin


‘insideables’

‘wearables’



Try-outs at REshape Center of Health(care) Innovation

Lucien Engelen

… but not all data is useful data !

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?


Translation is key in personalized health(care)

Personal profile data

Knowledge

Understanding

Decision

Action


Translation is key in Personalized Healthcare !

“I’m afraid you’re

suffering from an

increased IL-1β and

an aberrant miR843

expression”

Adapted from:

?


Personalized health(care) model Personalized Intervention

of patients-like-me Personal thresholds of persons-like-me

Big Biomarker Data

Molecular Non-molecular Environment …

Ho

meo

sta

sis

A

llo

sta

sis

D

isease

Time

Disease

Health

Selfmonitoring

Adapted from Jan van der Greef, TNO

Personal profile

Personalized health

Personalized medicine

{See eg Chen … Snyder, Cell 2012, 148: 1293}


Need for optimal quality in health biomarker analyses

Test, interpret, advice

“Post-traumatic Test Syndrome” ?


Personalized health(care) monitoring as part of our lives

• Monitor on background

• Alert when you are at risk

• Advice what to do

Examples from car dashboard:

• Empty gas tank

• Traffic jam ahead


http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRxqFQoTCJ6kuJXIvcYCFYFcFAodO2oP3A&url=http://arstechnica.com/apple/2014/03/ios-in-the-car-becomes-carplay-coming-to-select-dashboards-this-year/&ei=TsSVVZ7FO4G5UbvUveAN&bvm=bv.96952980,d.d24&psig=AFQjCNHK-5180CQ5Wim0GGTOe8N0tIZRIQ&ust=1435964869551370

View in the (very near) future


scanadu.m4v

Acknowledgements

Ron Wevers

Jolein Gloerich

Hans Wessels

Dirk Lefeber

Monique Scherpenzeel

Leo Kluijtmans

Lucien Engelen

Nathalie Bovy

Paul Smits

Maroeska Rovers

Bas Bloem

the Technology Centers

and many others

www.radboudumc.nl/personalizedhealthcare

www.radboudresearchfacilities.nl

www.radboudumc.nl/research/technologycenters

[email protected]

[email protected]

www.linkedIn.com

www.slideshare.net/alainvangool

Many collaborators and funders

Jan van der Greef

Ben van Ommen

Bas Kremer

Lars Verschuren

Ivana Bobeldijk

Marjan van Erk

Carina de Jongh

Peter van Dijken

Peter Wielinga

Robert Kleemann

Suzan Wopereis

and many others

CarTarDis


http://www.erasmusmc.nl/index.htm