Targeting EGFR Signal Transduction Pathway by Anticancer Drugs

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Targeting EGFR Signal Transduction Pathway by
Anticancer Drugs

• First Infobiomed Training Challenge,
  Barcelona/Villadrau
• Ignasi Belda
• Marilena Garefalaki
• Mark McAuley
• Eva van Soest
• Karin Pike-Overzet

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Group members

• Ignasi, Spain Drug design
• Marilena, Greece Biology
• Mark, Ireland Mathematical modeling
• Eva, the Netherlands Epidemiology
• Karin, the Netherlands Immunology

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Why targeting EGFR signaling pathway?

• Implicated in multiple human cancers
• Can promote multiple properties of neoplastic
  cells- proliferation, migration, angiogenesis,
  stromal invasion, resistance to apoptosis
• Hyperactivation mechanisms
• Autocrine secretory loop (ligand overproduction)
• Paracrine growth ligand produced by adjacent
  cells
• Constitutive receptor activation

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Initial contributions

• Biologist general introduction pathway
• Epidemiologist overview clinical drug testing
• Immunologist Micro-array data analysis
• Mathematical modeler overview basic modeling
• Drug designer drug designing strategies

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Process of finding the target

• 4 segments of the pathway to target
• Ligands
• Receptor
• Intracellular cascade
• Tyrosine kinase inhibitor
• Other inhibitors
• Transciption factors
• What has been done? What worked? What didnt
  work? Why not?

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Sources of information

• Group-member knowledge
• Pubmed for literature
• Microarray Databases
• In-house expertise
• External contacts
• Colleagues
• Author of interesting papers
• Modeling Software Systems Biology Markup
  Language (MathSBML)

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Ligands

• Advantages
• Accessible target
• Not published yet (structure and mechanisms
  recently solved)
• Structural similarities
• Immunoresponse-derived side-effect not expected

• Disadvantages
• Expected side-effects (systemic presence)

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Receptor/Antibody therapy

• Advantages
• Clinical data available
• Overexpression in cancer
• Extracellular

• Disadvantages
• With use of antibodies side-effects
• Low response rate
• Not novel

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Intracellular cascade
Tyrosine kinase inhibitors/others

• Disadvantages
• Low response rate in clinical trials
• One membrane to cross
• Alternative pathway resistance (temporary
  response)

• Advantages
• Clinical information available
• Promising in in vitro experiments
• Expression data available

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Transcription factors

• Advantages
• Novel

• Disadvantages
• Two membranes to cross
• No data to proceed

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Focusing on a novel approach

• Ligands (target known)
• Expertise epidemiologist, biologist, drug
  designer
• Signaling cascade (target unknown)
• Expertise immunologist, mathematical modeler
• Brainstorm and feedback regularly together

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Target 1 ligand
Marmor et al., 2004
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Mathematical modeling

• Rationale
• Representation of dynamics of ligand binding,
  internalization and degradation
• Establishing of links between physiological
  responses and levels of receptor activation
• Tool for decision making
• Optimal set of ligands to target balance
• As little blocking as possible
• As much effect as possible

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Receptors
RL complexes
Dimers
Ligands
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Biological approach

• Certain ligand expression is tissue dependent
• Overexpression of EGFR1, EGFR2, EGF-like ligands
  in solid tumors

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Drug design approach

• Design strategies
• Structure-based design
• De novo virtual drug design
• Combinatorial chemistry Chemical Graph
  Identifier QSAR
• High-throughput screening of natural products

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Drug design approach

• In vivo model and test
• Knock-in models
• Induced cancer
• Toxicity immune response studies

• In vitro model and test
• Binding assays
• Micro-calorimetry
• Surface plasmon resonance
• NMR (chemical shifts)
• Cellular experiments
• Inhibition experiments
• Toxicity
• Degradation experiments

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Drug delivery perspective

• Organ specific delivery to minimize side-effects,
  e.g.
• Lung
• Inhaling delivery techniques
• Organ specific proteases to activate pro-drugs
  (e.g. Human L-Capsine)
• Brain
• Blood-brain barrier crossing drugs

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Summary
Cell Biology
Mathematical model
Target selection
Drug design
(Pre)clinical testing
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Target 2 EGFR signal transduction pathway
A comprehensive pathway map of epidermal growth
factor receptor signaling Kanae Oda et al.
Molecular Systems Biology doi 10.1038/msb4100014
published online 25 May 2005
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Micro array technology
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Strategy for finding new targets in the EGFR
pathway
Databases
PathwayAssist, SCIpath
(www.sbml.org)
Visually
(Structure based) Drug design
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Expression data visualized in a pathway
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Problems and solutions
Feasible approach for target identification
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Advice for future training challenges

• Know general background of other participants
• Proper introduction of experts
• Emphasize the challenge rather than the
  competitions

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Lessons learned

• Easier than expected to work with scientists from
  different research fields
• Creative ideas arise from interdisciplinary
  discussions
• Unstructured distributed leadership works

Future collaborations

• Ask advice in different disciplines

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Thank you INFOBIOMED!