Joint Research Centre - easl.eu€™s Institute for Health and Consumer Protection ... Joint Research Centre The European Commission ... 27 Commission Members Director-General DG

Disclaimer: The contents of this presentation are the views of the author and do not necessarily represent an official position of the European Commission Disclaimer: The contents of this presentation are the views of the author and do not necessarily represent an official position of the European Commission

JRC Activities in Cancer and Rare Diseases

Ciaran NICHOLL

Public Health Policy Support – Unit Head

JRC’s Institute for Health and Consumer Protection (JRC-IHCP)

www.jrc.ec.europa.eu

Joint Research Centre The European Commission’s in-house science service


The JRC in the European Commission

Commissioner

Máire Geoghegan-Quinn

Research, Innovation & Science

President

José Manuel Barroso

27 Commission Members

DG Research & Innovation (RTD) Director-General

Dominique Ristori

Joint Research Centre

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To provide customer-driven scientific and technical support for the conception, development, implementation and monitoring of EU policies. As a service of the European Commission, the JRC functions as a reference centre of science and technology for the Union. Close to the policy-making process, it serves the common interest of the Member States, while being independent of special interests, whether private or national.

The Mission of the Joint Research Centre

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JRC in a Nutshell

• Since 1957 • 7 Institutes in 5 Member States • 2900 Staff (1/3rd temporary) • Budget EUR 360m/year, earn 15% competitive • S&T support to all stages of the EU policy making cycle

IRMM

ITU

IHCP

IES

IET

IPSC

IPTS ISM

HQ

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• Cancer Policy Support

• Nutrition (Prevention)

• Behavioural Sciences/Economics

• Medical Devices

• Genomics and Rare Diseases

www.jrc.ec.europa.eu

Public Health Policy Support


• Close proximity to the EU Decision Makers – use the health registry data to anticipate (trends) and guide policy interventions at both National and EU levels

• Reputation in harmonisation, standardisation (science base) and consensus building of scientific models and data systems

• Independence of all national/private/commercial interests • Provide continuity and sustainability (instead of short term contracts)

• Networking, engaging stakeholders/experts, consensus building

• Flexibility to adapt/grow according to future needs

• Facilitator, coordinator and scientific-policy partner for cancer care

JRC Added Value – Health Data/Information


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A mandate to improve health care in Europe Two projects of direct relevance: 1. Maintenance, development, harmonisation and use of European

cancer registies' data

2. Establish an EU platform for Rare Diseases

Health Data Projects


In 2012, JRC-IHCP took over the secretariat of the ENCR (European

Network of Cancer Registries, since 25 yrs) and will now:

- maintain and further develop the European Cancer Data at its location (IARC)

for a transition period of 3 years while mirroring the data architecture to the JRC

- In this 3 year period the JRC will involve and integrate and build upon the work

of important stakeholders (e.g. EUROCARE, CONCORDE, EUROCOURSE, EPAAC,

etc.)

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1. European Cancer Registries' Data 1/2


- In this 3 year period the JRC will harmonise data protocols (downloadable

software for data treatment, agreement on metadata standards, facilitate

competence building, exchanges of best practices, etc.)

- In this 3 years the JRC will analyse, publish and disseminate the data

(European cancer data is presently referred to as a ‘data graveyard’) in the form

of key messages to benefit both National and EU health care policy making (via

flash reports, factsheets, newsletters, web announcements, conferences, etc.)

- After 3 years the European data (from over 200 cancer registries) will be

located at the JRC

- view to developing a scalable architecture for health information (rare

diseases)

1. European Cancer Registries' Data 2/2


Establish an EU platform for Rare Disease Registries at JRC-Ispra - Over 600 Rare Disease Registries - Problem of heterogeneity – need for standardisation & harmonisation European Research Infrastructure Consortium (ERIC) - Meetings in June to develop concept and map out way forward

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2. Rare Disease Registries' Data 1/1


Thank you for your attention


Adverse Outcome Pathway (AOP) A conceptual construct that portrays existing knowledge concerning the pathway of

causal linkages between a molecular initiating event and a final adverse effect at a

biological level of organisation that is relevant to a regulatory decision (Ankley 2010).

AOPs incorporate the toxicity pathway and mode of action for an adverse effect

Exposure

Molecular

Initiating

Event

Organelle

Effects

Cellular

Effects

Tissue

Effects

Organ

Response

Individual

Response

Population

Response

Toxicity Pathway

Mode of Action

Adverse Outcome Pathway


Why map AOPs?

Advances in toxicogenomics, bioinformatics, systems biology and computational toxicology

PURPOSES:

• Understanding – pathway elucidation

• Classification – chemical categories (read-across)

• Risk Assessment - integrated testing strategy

Synthesis of data and knowledge from multiple levels of biological

organization

Identification of knowledge gaps and uncertainties

Facilitation of communication

Development of predictive models

Initially depicted as linear processes, the amount of detail and linearity is

depending on existing knowledge and risk assessment needs.


AOP Development Project

“From Protein Alkylation to Liver Fibrosis”

Brigitte Landesmann Joint Research Centre European Commission


Flow Diagram

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell

activationLiver fibrosis

Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level

MIE Tissue Level Organ Level

Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties


Adverse Outcome - Liver Fibrosis

A reversible wound healing response to a variety of chronic injuries

including toxic injury from chemicals.

• sustained production of growth factors and fibrogenic cytokines

• inflammation, tissue destruction, and repair processes simultaneously

• imbalance between deposition and degradation of extracellular matrix

(ECM) and change of ECM composition.

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell


Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level


Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties


Molecular Initiating Event - Protein Alkylation

Protein alkylation means the addition of an alkyl group to a protein amino

acid. Alkylating agents are able to draw up covalent bonds.

Protein alkylation disturbs the cellular redox balance, which leads to

disruption of multiple biochemical pathways in exposed cells, which in

turn

can trigger the death of exposed cells via either apoptosis and/or

necrosis.

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell


Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level


Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties


Key Event on cellular level

Hepatocyte Injury and Apoptosis/Necrosis

Hepatocytes are damaged by covalent binding to liver proteins and lipid peroxidation,

accompanied by oxidative stress and mitochondrial damage. Collapse of

mitochondrial membrane potential triggers apoptotic cell death. Apoptotic

hepatocytes undergo genomic DNA fragmentation and formation of apoptotic bodies.

Damaged hepatocytes release reactive oxygen species (ROS), cytokines (like TGF-b1, TNF-a)

and chemokines.

This leads to oxidative stress, inflammatory signaling and activation of KCs, HSCs, endothelial

cells and platelets.

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell


Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level


Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties



Hepatic Macrophage (Kupffer Cell) Activation

Following engulfment of apoptotic bodies Kupffer cells (KCs) become activated.

Activated KCs are a major source of cytokines (most importantly of TGF-b1)

chemokines,

lysosomal and proteolytic enzymes

ROS.

This leads to oxidative stress and inflammatory signaling.

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell


Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level


Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties



TGF-b1 expression

TGF-b1 is a key mediator and the most pro-fibrotic cytokine mediating a cross-

talk between parenchymal, inflammatory and collagen expressing cells.

TGF-b1 directly activates HSCs,

regulates the activation of growth factors,

stimulates the synthesis of multiple ECM proteins (including collagen) and

inhibits ECM degradation.

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell


Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level


Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties



Hepatic Stellate Cell (HSC) Activation

Activated HSCs proliferate, increase their contractility,

express new receptors and new proteins,

produce and deposit collagenous ECM,

produce cytokines, ROS and

amplify inflammation.

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell


Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level


Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties


Key Event on tissue level Progressive Collagen Accumulation and

Changes in ECM Composition

Changes in ECM composition directly stimulate fibrogenesis.

ECM provides a reservoir for growth factors

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell


Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level


Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties


Key Event related to various levels Oxidative Stress

ROS generation from hepatocytes, KCs, HSCs, inflammatory cells

Oxidative stress contributes to hepatocyte apoptosis,

KC activation,

HSC activation,

macrophage activation and inflammation.

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell


Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level


Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties


Key Event related to various levels Chronic Inflammation

Inflammatory signaling from injured hepatocytes, activated KCs and HSCs

Chronic inflammation contributes to hepatocyte injury,

KC activation,

HSC activation,

ECM production and remodeling,

oxidative stress.

Oxidative stress

Inflammation

Protein-

Alkylation

Covalent Protein

binding

TGF-b1

expression

Kupffer cell

Activation

Stellate cell


Collagen

accumulation

Changes in

ECM

composition

Hepatocyte

Injury

Apoptosis

Cellular Level


Parent

compound or

metabolite

capable of

alkylating

proteins

Chemical

Structure &

Properties


Relevance

Any chemical causing submassive hepatocellular injury may cause

liver fibrosis and the systemic response may equally damage other

organs and tissues.

Fibrosis may also affect lung, kidney, heart and blood vessels, eye,

skin, pancreas, intestine, brain and bone marrow.

Also multi-organ fibrosis is possible (due to mechanic, chemical or

radiation injury).

The described findings in liver fibrosis parallel those in studies of

fibrogenesis in the other organs.

Findings also suggest common conserved pathways concerning the

initiation and modulation of liver fibrosis across different species.


Thank you for your attention

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Joint Research Centre - easl.eu€™s Institute for Health and Consumer Protection ... Joint Research Centre The European Commission ... 27 Commission Members Director-General DG