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Expert center as a private public partnership ‐ The complexity ofpartnership ‐ The complexity of technologies in an SME structure
for expert centersThTh E tE t ii‐‐ The The EuroproteomeEuroproteome experienceexperience‐‐
Dr Paul von HoegenDr. Paul von HoegenManaging Director
Euraccine Consulting GroupBrussels, Belgium
Euraccine_be@yahoo.com
+32 475 913572
Experience as CSO EuroproteomeExperience as CSO Europroteome
Colon Cancer Biobank for marker/targetColon Cancer Biobank for marker/target discovery with patient history and outcome
predictionp• Academic network: High fluctuation – constant training• Needed samples rare – create meaningful patient groups• Technologies constant development and changes from• Technologies – constant development and changes fromproviders: Need to generate internal standards
•Drug targets, biomarker, diagnostics, individualized therapyd f• Complexity: Multiple technologies and Integration of
Bioinformatics (PhaseIt)• Investors and Industry clients: Wanted to see ready togo Biobank; No patients to build Biobank
• Improve management of expectations
2Euraccine Consulting Group (Brussels) ‐ Paul von Hoegen
Pharma’s Needs 2003+
NeedsNeeds
• Anything that reduces development risk, time & costs: FAIL EARLY – FAIL CHEAP
• Priorisation of (genomically derived) targets (500 –5,000) to deal with the VALIDATION BOTTLENECK
• COMPOUNDS
• VALIDATED cancer targets (in vitro and in vivo) with link to a PATHWAY
• Diagnostic bio-markers related to clinical OUTCOME
• Identification of risk groups with ADVERSE EVENTS
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Patient Centered SolutionsPatient Centered SolutionsDIAGNOSTICS THERAPY FOLLOW UP
DEVELOPMENT
Responder ProfilingOncoAssist
Disease Marker
Biomarker
Screening Assays Follow Up
Therapy Control
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
CCN: Large Scientific Networkg
• Outstanding scientific and
Berlin (Berlin (HennigsdorfHennigsdorf))
• Outstanding scientific and medical expertise as sounding board for research results
MagdeburgMagdeburgDortmundDortmund
KielKiel
Berlin (Berlin (CharitéCharité))
HamburgHamburg
StettinStettin • „Breeding & sourcing ground“ for high‐calibre
GenevaGenevaCottbusCottbus
LeipzigLeipzig
LausanneLausanne
RennesRennes
(( ))
MagdeburgMagdeburgStuttgartStuttgart
ground for high calibre product approaches
• Access to human tissue
ErlangenErlangen
GenevaGeneva LeipzigLeipzigHalleHalle
LyonLyon
• Access to human tissue samples, pathology and related patient data
GrenobleGrenoble
BolognaBologna
ZurichZurich C C N
ChileChileBolognaBologna
THE CLINICAL CANCER NETWORK
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Sampling
• Patients consentPrior to surgery
Surgery Pathology *Histology Pathological findings
Patients consent• Blood sampling; Stool sampling
• Grading
g y gy Histology Pathological findings
• pTNM (UICC)
• etc.
*Cell sampling
* Photos of kidney tissue/cells by Prof. F. Dombrowski, Pathology, Magdeburg
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Human Tissue Sample Bankp
5.000
6.000s
3 000
4.000
f Sam
ples
2.000
3.000
umbe
r of
0
1.000N
TimeJan 01 Jan 02 Jan 03
Status as of March 10, 2003 Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
FeaturesO N C O T R A C KCLINICAL CANCER RECORDS &
OUTCOMES DATABASEOUTCOMES DATABASE
Colon, Stomach & Pancreas Cancer (number of variables)Cancer (number of variables)
• Anamnesis and Diagnostics (48)• Surgery & Therapy (50)Surgery & Therapy (50)• Pathology (103)
• Follow Up (21)• Follow Up (21)• Local Recurrence (10)• Distant Metastasis (6)Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Cell Samples/Organp / g
Number of Patients:
Rectum
ColonNumber of Patients:
Liver
Stomach
Pancreas
Lung
Oesphagus
Small Bowel
Pancreas
Kidney
Oesphagus
plus ovar, bone, gallbladder
Status as of March 10, 2003 Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Research Matrix: Technologiesg
IDENTIFICATION CHARAC- VALIDATIONIDENTIFICATION TERIZATION VALIDATION
B I O I N F O R M A T I C S
2D-PAGE
MASS SPECMASS SPEC
CIPHERGEN SELDI
DNA MICRO ARRAY & ROSETTA RESOLVER
PROTEIN CHEMISTRY
RT-PCR
CELL CULTURE
YEAST-2-HYBRIDYEAST-2-HYBRID
BIACORE
Si RNA
R E S O U R C E M A N A G E M E N TDr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Technologies for Cancer Target Identification via 2D‐PAGE & MS
SDS‐PAGEIEF ScanningStainingIEF
Image Analysis Spot Picking MS AnalysisImage Analysis
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Colon Cancer Gene Expression Analyses: Proof of Concept
MD
134
109
MD
149
MD
150
87M
D13
5M
D82
118
97M
D13
314
195 11
386
MD
121
174
139
112
171
106 20 CRC Patients
M C M M C M M C C9
M C C9
E1 C M C C E 1 C E 1
EP-03-01 MYCTIMP1GAPDH
(DD Mode)
GAPDHCA1FABP1 KRT19KRT20KRT20MUC2CEACAM1
EP-03-01: Induced transmembrane proteinMYC: myc oncogeneTIMP1: Tissue inhibitor of metalloproteinases 1GAPDH: Glycerolaldehyde-3-phosphate dehydrogenase
Color Range Scale
U l t d dehydrogenaseCA1: Carbonic anhydraseFABP1: Liver fatty acid binding protein KRT19: Cytokeratin 19KRT20: Cytokeratin 20MUC2: Mucin 2
Up-regulated
Down-regulated
No gene regulation
*Literature data are from human colon cancer tissue DNA microarray, SAGE and Northern blot experiments
MUC2: Mucin 2CEACAM1: CEA related adhesion molecule 1
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
… Combining Proteomics & TranscriptomicsTranscriptomics
• 2D PAGE Data• Gene Profiling Data
MD
134
C10
9M
D14
9M
D15
0C
87M
D13
5M
D82
C11
8C
97M
D13
3C
141
C95
E113
C86
MD
121
C17
4C
139
E112
C17
1E1
06
CA1KRT20
KRT20
C C C C C C C C C C
CA1FABP1 KRT20
FABP1
Color Range Scale Up-regulated
Down-regulated
pH 5-8; patient tumor sample
No gene regulation
SwissProt # Protein name2D PAGE data DNA array/SAGE data 2D PAGE DNA array
P00915 Carbonic anhydrase I (CA1) down down up/down up/downP07148 Liver fatty acid binding protein (FABP1) down down down downP35900 Keratin cytoskeletal 20 (KRT20) down down up/down down
EP dataLiterature* reported data
y ( )
* Literature data are from the experiments with human colon cancer tissue
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Colon / Metastasis Screen
Colon Rectum Colon RectumTissue Serum
Colon Rectum Colon Rectumwith metastasis 6 3 20 0without metastasis 12 8 16 0
number of patients
Colorectal cancer specimens
Serum Transcriptomics ProteomicsSerum Transcriptomics Proteomics
d ff 223 diff37 differences 289 differences(2 fold change;p‐value < 0.01)
223 differences(2 fold change;40% frequency)
FPLC/HPLC Identification In silico validation In silico validation
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Classification of regulated proteins (Wh d h t?)(Who needs what?)
Proteases5%
Kinases1%
Ribosomal1%
Cytokeratins4%
OtherStructural/Cell
adhesion12%
Transport/ P i /
Immunoglobulines
Nucleic Acid Binding
2%
11%
Processing/ Chaperone Function
10%
(and related)5%
EnzymesEnzymes49%
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Target Identification & SelectionTarget Identification & SelectionWill vary for each application (client), combined with bioinformatics
3Extensive annotation and
project potential
10 Complex annotation, Target profile
> 50DNA Array,
Bioinformatics
Target profile
50
2D MS
Bioinformatics
> 350 2D, MS
# of Targets (example)Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Research Matrix: Technologiesg
IDENTIFICATION CHARAC- VALIDATIONIDENTIFICATION TERIZATION VALIDATION
B I O I N F O R M A T I C S
2D-PAGE
MASS SPECMASS SPEC
CIPHERGEN SELDI
DNA MICRO ARRAY & ROSETTA RESOLVER
PROTEIN CHEMISTRY
RT-PCR
CELL CULTURE
YEAST-2-HYBRIDYEAST-2-HYBRID
BIACORE
Si RNA
R E S O U R C E M A N A G E M E N TDr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Cancer Target ValidationCancer Target ValidationBinding Partners (BiaCore) Yeast Culture (Y‐2‐H)
Cell Culture (siRNA, anti sense)Data Integration
Cell Culture (siRNA, anti sense)
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Validation: The Technology Wheel2D gels
Validation: The Technology WheelAntibodies 2D gels
Mass Yeast 2Hybrid
SpectrometryHybrid
12
3
RNAi
>350
48DNA ArraysRT PCR
RNAi
CyphergenDr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Cancer Target Discovery StatusCancer Target Discovery Status
Membrane TargetsSeldi Markers Stomach/Colon
3Colon Metastasis
12
3
350
48
Stomach
> 350
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Colorectal Cancer: Gene Expression Breakdown by UICC Stage*
• Pre‐UICC Stage III– 112 preferred marker genes expressed– 112 preferred marker genes expressed
• UICC Stage III319 f d k d– 319 preferred marker genes expressed
• UICC Stage IV– 907 preferred marker genes expressed
Up/Down ratio: Clearly negative
*preliminary data based on a limited no. of analysed samples
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
… as Tool for Functional Target Validation
100
Validation
UICC stage I
60
70
80
90Risk 0Risk 1UICC I
ival
• Decision system based on artificial intelligence
UICC stage I
30
40
50
60
Perc
ent S
urv
• Classification of high‐risk patients for distant metastasis possible
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 2040
10
20
Survival (months)100
Ri k 0
• Based on only 6 clinical parameters
60
70
80
90Risk 0Risk 1UICC II
viva
l
• Tool to be positioned to identify high‐risk patients in Stage I & II
UICC stage II
30
40
50
Perc
ent S
urv
• Discussions with pharma companies for application
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 2040
10
20
Survival (months)
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
From Disease Centered Biobank Research ..
Seldi Proteins HistopathologyCytosolic Proteins
Membrane Proteins
HLA- assoc. Peptides Clinical Data
tumor cell
cDNA Microarray
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
To Patient Centered Solutions...To Patient Centered SolutionsDIAGNOSTICS THERAPY FOLLOW UP
DEVELOPMENTPROGNOSTICS
Responder ProfilingOncoAssist
Disease MarkerO N C O T R A C K O N C O A S S I S TCLINICAL CANCER RECORDS &
OUTCOMES DATABASE CANCER OUTCOME PREDICTION & STRATIFICATION
Screening Assays Follow UpO N C O P R E P C C N
Therapy Control
CANCER CELL PURIFICATION THE CLINICAL CANCER NETWORK
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Life event history calendar for collecting d il d i i f idetailed patient information
Standardized set of cues offer conceptualStandardized set of cues offer conceptual anchors (such as important life themes or domains, e.g., life relationships, jobs, residences, etc.) and encourage top‐down , ) g pprocessing.
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
LEHC: Parallel Processing of patient information: Complete history of lifestyle and disease possibleComplete history of lifestyle and disease possible
Parallel processing : balanced visual organization allows the individual to look atorganization allows the individual to look at the display, use cues from their own life, and remember events base on their interrelationships between domains.
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
interrelationships between domains.
Expectations / Ideas / Challengesp / / g
•Integrate all players (patients, ethics academic, agencies, serviceg p y (p , , g ,provider and end-user)•Assure long time engagement under constant conditions•Manage change and integration of new technologiesManage change and integration of new technologies•Multiple platforms for identification and validation•Individual marker versus patterns – making the choice•Standards and reference samples for ring validations•Priorities for sample distributions? How to conserve thematerial best for the future?
•Longitudinal follow up of disease markers (same patient)•Links to clinical trials and treatment outcome•Foresee the needs of the future (of the partners)•Foresee the needs of the future (of the partners)
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Biotech, Start upsStart ups
Biotech exampleTechnology AcademicTechnology providers
Academic Research
Dr. Paul von Hoegen Euraccine Consulting Group (Brussels)
Need of strong Core AssetsNeed of strong Core Assets
BBMRI
ality
dentia
Confid
CDr. Paul von Hoegen Euraccine Consulting Group (Brussels)
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