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Modeling of Acute resistance to the HER2 inhibitor_ lapatinib

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Modeling of Acute resistance to the HER2 inhibitor_ lapatinib Powered By Docstoc
					Analysis of inhibition of HER2
        signaling to apoptotic
         transcription factors

            Marc Fink & Yan Liu & Shangying Wang
                          Student Project Proposal
                   Computational Cell Biology 2012
Goals
- Modeling the signaling pathway of HER2 inhibitor,
  Lapatinib, in Breast Cancer Cells

- Analyze the influence factors of cell apoptosis

- Explanation of cell survival rate after treatment
Outline
— Brief review

— Boolean network model and results

— Modeling with ODEs in VCell and COPASI

— Analysis of simulation results

— Summary and outlook
Mechanistic (process) diagrams
        HER2
                     Lapatinib
                                                        Death ??????
                    PI3K                                   Survival
                           PDK1
                p
            AKT (PKB)                                      Protein
 p                                                         Translation
                                                   ER
FoxO p                      FoxO
  p 14-3-3
                               Translocation                        Translocation

 FoxO       FoxO                   Transcription
                           Apoptotic
                           genes                        Apoptosis

     FoxO    FoxO           Survival
                            genes                                          01/13
 Flow chart and strategies
       HER2        Lapatinib   IGF1R
                                       — Lack of experimental
                                         parameters
       AKT                     RAF       => Boolean network

                               MEK     — Better understanding of
       FoxO                              dynamics
                                         => ODEs
                               ERK
FASL                                   — Analysis of survival rate
                                         => Stochastic simulation
                               RSK
         BIM
                               BAD
       apoptosis                                                02/13
Boolean network model
  HER2         Lapatinib   IGF1R



  AKT




                                   Apoptosis
  FoxO




                                                 Time steps
     BIM                               => Average value of
                                       apoptosis is around 0.5 with
   apoptosis                           simplification.         03/13
  Boolean network model
       HER2        Lapatinib   IGF1R



       AKT




                                       Apoptosis
       FoxO



FASL
                                                     Time steps
         BIM                               => Average apoptosis is
                                           around 0.6 with additional
       apoptosis                           information.            03/13
  Boolean network model
       HER2        Lapatinib   IGF1R


                               RAF
       AKT




                                       Apoptosis
                               MEK
       FoxO

                               ERK
FASL
                               RSK                   Time steps
         BIM                               => Results depend on the
                               BAD         complexity, adding weights
       apoptosis                           not possible.          03/13
Modeling with ODEs




=> 22 species and 32 reactions, reasonable rates???!!!   04/13
Model reduction and modification
Due to the importance of FOXO
=> Neglect the downstream and add the self regulation




                                                        05/13
Model reduction and modification
               HER2        Lapatinib   IGF1R


               AKT                     RAF


                                       MEK
               FoxO

                                       ERK
        FASL
                                       RSK
                 BIM
                                       BAD
               apoptosis                       05/13
Model reduction and modification
Due to the importance of FOXO
=> Neglect the downstream and add the self regulation

  HER2      Lapatinib
                              HER2_dimer

                              HER2_dimer*             PI3K
  AKT
                                           H_PI3K
  FoxO                                                 PIP3
                                    PIP2

Apoptosis                                     AKT             AKT*

                               Φ                      Φ
FoxO_gene           FoxO_mRNA (x)          FoxO (y)            FoxO* (z)
Model reduction and modification
Due to the importance of FOXO
=> Neglect the downstream and add the self regulation

  HER2      Lapatinib                           [Birtwistle et al., 2007]
                              HER2_dimer

                              HER2_dimer*             PI3K
  AKT
                                           H_PI3K
  FoxO                                                 PIP3
                                    PIP2

Apoptosis                                     AKT             AKT*

                               Φ                      Φ
FoxO_gene           FoxO_mRNA (x)          FoxO (y)            FoxO* (z)
 Self regulation of FOXO
                               Φ                    Φ
FoxO_gene          FoxO_mRNA (x)         FoxO (y)       FoxO* (z)




 => Bistability of the positive feedback loop                   06/13
Modified model




=> 14 species and 16 reactions   07/13
 Sensitivity analysis in COPASI

Binding of
Laptinib to
HER2




   Dimerization of HER2
                                                 FOXO




 => Laptinib is important for cancer cell apoptosis     08/13
Analysis of simulation results
— Deterministic simulations with parameter scan (Laptinib)
                   FOXO concentration




                               With increasing
                               initial Laptinib
                               concentration
                               0 -> 400 nM




                                                         09/13
Analysis of simulation results
— Deterministic simulations with parameter scan (Laptinib)



                   Phosphorylation




=> Laptinib is able to stimulate FOXO, crucial to apoptosis 09/13
Analysis of simulation results
— Random initial concentrations and constant Laptinib (200nM)
                    FOXO concentration




=> Initial concentrations influence the effect of Laptinib. 10/13
Analysis of simulation results
— Stochastic simulation using Gillespie algorithm (in VCell & C)
             High Laptinib




                                                  Low Laptinib




                                                            11/13
Summary and outlook
— Inhibition of HER2 signaling to apoptotic transcription factors
  is studied.

— Models with different complexities are analyzed.

— Laptinib induced inhibition of HER2 is simulated.

Outlook

— Improve the stochastic study

— Improve the pathway model with more details by getting
  more rates from experiments

— Measurement of concentrations within small time scale
  before and after treatment will help to understand the whole
  signaling process and validate the model.
                                                                    12/13
Experience with the softwares
                             COPASI   vs   VCell

— Writing reactions            +           +++

— Checking parameters          +           +++

— Deterministic simulation    +++           +

— Stochastic simulation       ++            +

— Parameter scan              +++           ++

— Sensitivity analysis        +++           -

— Visualization                -           +++

                                                   13/13
Happy Birthday
   to Nina!

				
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posted:7/15/2014
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