Download Modeling of Acute resistance to the HER2 inhibitor

Modeling of Acute
Resistance to the HER2
Inhibitor, Lapatinib, in
Breast Cancer Cells
Marc Fink & Yan Liu & Shangying Wang
Student Project Proposal
Computational Cell Biology 2012
Outline
 Brief review of the project goal
 Boolean network model and results
 Modeling with ODEs in VCell and COPASI
 Analysis of cell survival rate
 Summary and outlook
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
01/13
Mechanistic (process) diagrams
Death ??????
Survival
Lapatinib
HER2
PI3K
p
PDK1
AKT (PKB)
p
FoxO p
p 14-3-3
FoxO
FoxO
FoxO
FoxO
FoxO
ER
Protein
Translation
Translocation
Transcription
Apoptotic
genes
Survival
genes
Translocation
Apoptosis
02/13
Flow chart and strategies
HER2
AKT
FoxO
Lapatinib
IGF1R
RAF
MEK
ERK
FASL
RSK
 Lack of experimental
parameters
=> Boolean network
 Better understanding of
dynamics
=> ODEs
 Analysis of survival rate
=> Stochastic simulation
BIM
BAD
apoptosis
03/13
Boolean network model
HER2
Lapatinib
IGF1R
FoxO
Apoptosis
AKT
Time steps
BIM
apoptosis
=> Average value of
apoptosis is around 0.5 with
simplification.
04/13
Boolean network model
HER2
Lapatinib
IGF1R
FoxO
Apoptosis
AKT
FASL
Time steps
BIM
apoptosis
=> Average apoptosis is
around 0.6 with additional
information.
04/13
Boolean network model
AKT
FoxO
Lapatinib
IGF1R
RAF
MEK
ERK
Apoptosis
HER2
FASL
RSK
BIM
BAD
apoptosis
Time steps
=> Results depend on the
complexity, adding weights
not possible.
04/13
Modeling with ODEs
=> 22 species and 32 reactions, reasonable rates???!!!
05/13
Model reduction and modification
Due to the importance of FOXO
=> Neglect the downstream and add the self regulation
HER2
AKT
FoxO
Apoptosis
Lapatinib
Self regulation of FOXO
Φ
FoxO_gene
FoxO_mRNA (x)
Φ
FoxO (y)
=> Bistability of the positive feedback loop
FoxO* (z)
06/13
Modified model
=> 14 species and 16 reactions
07/13
Sensitivity analysis
Binding of
Laptinib to
HER2
Dimerization of HER2
FOXO
=> Laptinib is important for cancer cell apoptosis
08/13
Modeling with ODEs IV
Deterministic simulations with parameter scan (Laptinib)
=> Laptinib is able to stimulate FOXO, crucial to apoptosis 09/13
Analysis of cell survival rate
 Random initial concentrations (with COPASI)
=> Laptinib is able to stimulate cancer cell apoptosis
10/13
Analysis of cell survival rate
 Stochastic simulation (with VCell and C)
=> Laptinib is able to stimulate cancer cell apoptosis
11/13
Summary and outlook
 Apoptosis pathway of breast cancer cell is modeled and
analyzed with simplifications
 Survival rate of cancer cell is analyzed
 Laptinib induced cancer cell apoptosis is with certain
probability
Outlook
 Improve the pathway model with more details by
getting more rates from experiments
 Validation of the model and survival rate
12/13
Experience with the softwares
COPASI
vs
VCell
 Writing reactions
+
+++
 Checking parameters
+
+++
 Deterministic simulation
+++
+
 Stochastic simulation
++
+
 Parameter scan
+++
++
 Sensitivity analysis
+++
-
-
+++
 Visualization
13/13
Thank you for your attention!