Novel complex models for cancer target validation

Novel complex models for cancer target
validation - the PREDECT project
Emmy W. Verschuren, PhD
FIMM-EMBL Group Leader
IMI2 Info Day 2014
26.08.2014
© FIMM - Institute for Molecular Medicine Finland
www.fimm.fi
PREDECT Answered the 2009 Call
Topic 1 New tools for target validation to improve drug efficacy
26 eligible proposals
Topic 2
Molecular biomarkers
27 eligible proposals
Topic 3
Imaging biomarkers for anticancer drug development
10 eligible proposals
Academic Coordination of the IMI-PREDECT Consortium
1. FIMM Nordic EMBL Translational Institute
II. New consortium and research plans
III. Young and dynamic team
Approximate One Year Negotiation and Preparation Phase ...
• Spanning three major pathologies
• Integrated by bioinformatics and systems biology tools
Breas Prostat Lun
Bioinformatics and
Systems Biology
9 Academic
3 SME
7 EFPIA
WPL/CoL
20 Partners, 26 PIs, over 60 active
scientists + support personnel
Full project review by Scientific Review
committee in Brussels (July 2010)
Project Focus & Working GANNTs
Contact
Launch Meeting at Institute
Curie (March 2011)
Postdoc Recruitment
Campaign
Organisation
Expertise
David Tuveson
Cambridge
GEMMs & therapeutics
Pasi Jänne
Dana Farber
Cancer Institute
Lung cancer, efficacy of
EGFR targets
Andrew Ewald
Lawrence
Livermore
Johns Hopkins
In vitro complex models,
breast cancer
3D models, Imaging
Peter Sorger
MIT and Harvard
Systems Biology
Allan Balmain
UCSF
comprehensive
cancer center
Mouse genetics and prostate
cancer models
Mina Bissell
Organisational Structure & Committees
Telcons & Meetings
SAB Meeting at the AACR (April 2011)
∼ 20 M€
www.predect.eu
5 year project
(Feb 2011-2016)
Project & Grant Agreement
.. With an Effective Partner Communication & Decision Flow
MANAGEMENT
John Hickman DSc. (Servier)
Steve Wedge PhD. (AstraZeneca)
Emmy Verschuren PhD. (FIMM)
.. With an Effective Partner Communication & Decision Flow
MANAGEMENT
John Hickman DSc. (Servier)
Steve Wedge PhD. (AstraZeneca)
Ralph Graeser (Janssen)
Emmy Verschuren PhD. (FIMM)
.. With an Effective Partner Communication & Decision Flow
MANAGEMENT
9 PHARMA
John Hickman DSc. (Servier)
Steve Wedge PhD. (AstraZeneca)
Ralph Graeser (Janssen)
Emmy Verschuren PhD. (FIMM)
+
.. With an Effective Partner Communication & Decision Flow
MANAGEMENT
9 PHARMA
12 SME / ACADEMIA
+
1. FIMM & U. of Helsinki, FI
!
2.VTT, FI
!
3. Cardiff University, UK
!
4. EPFL, CH
!
5. Weizmann Institute, IL
!
6. Radboud U. Nijmegen Medical Center, NL
!
7. Erasmus U. Medical Center Rotterdam, NL
!
8. U. Tartu, EE
!
John Hickman DSc. (Servier)
Steve Wedge PhD. (AstraZeneca)
Ralph Graeser (Janssen)
Emmy Verschuren PhD. (FIMM)
9. Dr. Fischer-Bosch Institute for Clinical Pharmacology, DE
!
10. Biomedicum Genomics, FI
!
11. IBET, POR
!
12. Oncotest, GER
+
!
At UH: Emmy Verschuren, FIMM
Olli Kallioniemi, FIMM
Johan Lundin, FIMM
Juha Klefström, Inst. Biom.
Outi Monni, FuGu
Panu Kovanen, HUS
Network of European Scientists (∼25 PhDs/Postdocs)
!
www.predect.eu
Researchers: ~ 70 scientists in 26 labs in 12 EU countries includes more than 25 PhDs and Postdocs
Project Implementation
SC
MANAGEMENT TEAM
IPC
Chair: Hickman
Vice chair: Graeser
Chair: Hickman
Vice chair: Graeser
Members:
WPL, WP coL, legal
representatives
Members:
All partners
Members:
WPL, WP CoL
Project office
Decision making
(every 6 months)
Continual follow up
and guidance
PROJECT OFFICE
Advice
(every year)
Support
WPL + CoL
WPL + CoL
WPL + CoL
WP1 Breast
WP2 Prostate
SAB
EAB
Balmain, Bissell,
Ewald, Jänne,
Sorger, Tuveson
Forsse, Smith
Advice
(every 1.5 years)
Annual follow up and
guidance
WPL
WP3 Lung
WP5
Dissemination
WPL + CoL
WP4 Platforms, databases, bioinformatics and
systems biology
STEERING
HICKMAN
IMPLEMENTATION
MANAGING ENTITY OF
IMI JU FUNDING
VERSCHUREN
COORDINATION
IMI JU
PREDECT Scientific Advisory Board
Contact
Organisation
Expertise
David Tuveson
Cold Spring Harbor
Laboratory
Pancreatic cancer, GEMMs,
therapeutics
Pasi Jänne
Harvard
Lung cancer therapy
Mina Bissell
Lawrence Livermore
National Laboratory
In vitro complex models of breast
cancer
Andrew Ewald
Johns Hopkins
3D models, imaging,
morphogenesis
Allan Balmain
UCSF comprehensive
cancer center
Mouse genetics and cancer models
Two SAB meetings since 2011; next one planned for 2015
PREDECT Science Networking
PREDECT’s Mission
To validate NOVEL COMPLEX IN VITRO models, to improve on pre-clinical ONCOLOGY target DISCOVERY
‘Can we do better than xenografts or cells
grown on plastic ?’
Complex Models to Reduce Attrition Rates ?
PhRMA Annual Member Survey, 2011
“ re-structuring the flow-chart of drug discovery to provide early go/
no-go decisions on novel targets, so reducing attrition rates in clinical trials “
Assess Mice as Surrogate Cancer Models
❖
Widely studied mimic of human cancer (subtype)
❖
In vivo maintenance of human patient tumours ❖
Source for perturbable ex vivo organotypic models ❖
Continuous and relatively consistent supply of tumour tissue
Xenograft
Patient tumorgraft GEMM
PREDECT-validated in vitro target
validation models
Tissue Slices
3D / Bioreactor
Project Organisation
Pathologies and
Model platforms
!
!
Breast
Prostate
ER+
Mol.
Path.
!
CRPC
NSCLC
KRAS; LKB1
Tissue
Slices
3D
Mol. Models
Path.
!
In vivo
Models
Project Organisation
Pathologies and
Model platforms
!
!
Breast
Prostate
ER+
Mol.
Path.
!
CRPC
NSCLC
KRAS; LKB1
Comparative
Modelling
I. Mouse vs human
II. In vitro vs in vivo
III. Steady state vs perturbed
Tissue
Slices
3D
Mol. Models
Path.
!
In vivo
Models
The PREDECT Concept
Tissue Slices
3D Co-culture
3D Bioreactor
3D Spheroids
2D on Plastic
reconstruction
deconstruction
=
PREDECT starts at both ends of complexity, with stepwise increases / decreases
in complexity. Every step is compared to each other and primary tumors.
Collaborative Molecular Pathology Platform & TMA Biobank
Partner & EFPIA
clinical samples
2D on Plastic
3D in Matrix
3D Co-culture
3D Bioreactor
Tissue Slices
Mouse models
Towards Systems Pathology
!
FIMM TMA biobank
❖ Web Microscopy shared PREDECT portal
❖ Digital archive and data analysis
❖ Quantitative imaging of cellular responses
❖
Stainings with validated set of 20+ antibodies
to measure signaling, pathology, cell type, proliferation, stress
Olli Kallioniemi Johan Lundin
Shift from upward to
downward causation; functional
‘wiring’ of molecules
Towards Quantitative Model Validation
Antibody stainings
Quantitative Pathology Heatmap
LUNG CANCER
PROSTATE CANCER
BREAST CANCER
PREDECT Models
Outstanding Questions
!
❖ What does a go/no go look like, which read-outs are critical ? !❖
How will successful efforts be transferred to industry ?
Image Generation, Annotation and Analysis Pipeline
Partners Complex tissue samples
Bioinformaticians
Metadata archive
Molecular Pathologists and Biologists
TMA staining, Image digitisation
Olli Kallioniemi, Johan Lundin, Sami Blom, Nina Linder,
Yinhai Wang, Anne Grote,Tauno Metsalu, Jaak Vilo
Image Generation, Annotation and Analysis Pipeline
Partners Complex tissue samples
Bioinformaticians
Metadata archive
WebMicroscope Data Hub
vs
Molecular Pathologists and Biologists
TMA staining, Image digitisation
Visual
Automated image
analysis
http://vimeo.com/user21191613
Olli Kallioniemi, Johan Lundin, Sami Blom, Nina Linder,
Yinhai Wang, Anne Grote,Tauno Metsalu, Jaak Vilo
Rigorous Tissue Slice Culture Method Optimisation
Tumour collection
Slicing
Culture
Protein analysis
>> Do cultured slices mimic the biology of its in situ tumour (viability, proliferation, signalling)
• Culture method matters • Careful in vivo vs ex vivo analysis is required, and is not trivial
• Differential stress-related expression changes are reason for caution, but can now be
systematically taken into account
Emma Davies, Simon Barry, Hanneke van Zoggel,Wytske van Weerden, Meng
Dong, Matthias Gutekunst, Heiko van der Kuip, Katja Närhi, Emmy Verschuren
Stirred Bioreactor 3D Model Analysis
Functionality and heterogeneity of expression, here of the Estrogen
Receptor, can also be established by imaging.
TMA embedded
Confocal analysis
Catarina Brito, Marta Estrada,Vitor Santo,
Micheal Barbier,Yolanda Chong
Cross-Oncology Project Collaboration
Proximity Ligation Assay technology to probe wiring of
signalling pathways
Ola Söderberg, Uppsala University
PREDECT Impact
❖
Synergistic exchange of expertise on cancer modelling
!❖
Unique collaborative molecular pathology biobank platform established
!❖
Opportunity for industry to reach out to pre-clinical ‘hospitals’ worldwide (eg CAPR)
!❖
Interactions with other IMI and global Public-Private Partnerships, setting a standard
(eTRIKS, Oncotrack, Quic-Concept)
❖
!
Awareness on the power and limitations of the current preclinical pipeline
❖
Adoption of select complex models in project laboratories, and industry
PREDECT Project Challenges
!
❖
Harmonisation and Prioritisation
!❖
IP issues of using mouse models in industry
!❖
Sustainability of TMA-based pathology infrastructure
!❖
What are the measures of success; what will change practice in industry?
!❖
EFPIA partner long-term perspectives & company support
❖
Postdoc publication and career uncertainties
View towards Horizon 2020
Knowledge
Expectations
Ageing population
Patient empowerment
The right prevention and
treatment for the right
patient at the right time
‘Now is the time
for change’
!
!
Integration of multi-stakeholder interests
(scientific, technological, regulatory and healthcare)
€€’s
Acknowledgements
!
Orion-Farmos Research
Foundation
PREDECT Management
John Hickman DSc
For Servier
Ralph Graeser PhD
Laurence Lapôtre
Kurt Salmon
Janssen
And all IMI-PREDECT consortium partners for Collegiality, Dedication and Partnership!