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On Viable Strategy in Mathematical Model of Cancer Therapy
Alexander Bratus, Igor Samokhin Lomonosov Moscow State University BIOMAT 2017
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Problem Statement We study a dynamic optimization problem for a general nonlinear mathematical model for therapy of a lethal form of cancer. Let us denote: 𝐶 𝑡 − the number of cancer cells 𝑁 𝑡 − the number of normal cells 𝑔 𝑡 − the nutrition concentration (oxygen, glucose, etc.) ℎ 𝑡 −the concentration of the drug 𝑢 𝑡 − the measurable control function: 0≤𝑢 𝑡 ≤𝑀, 𝑀>0
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Problem Statement (1) The cell growth rates are determined by the Gompertz law: 𝑟 𝑖 𝐺 𝑔 = 𝑟 𝑖 𝑔 𝜈 𝑖 +𝑔 (2) The therapeutic agent (drug) is spread out through blood vessels 𝑑ℎ 𝑑𝑡 ~ 𝑔 𝑡 𝑢+…, 0≤𝑢 𝑡 ≤𝑀 (3) The negative influence of the drug: 𝑓 ℎ = 𝑘ℎ 𝑎+ℎ , 𝑘,𝑎>0 𝑓(ℎ) is a therapy function for cancer cells and the damage function for normal cells (4) The cancer and normal cells compete with each other for common resources −𝛽𝑁 𝑡 𝐶(𝑡) (5) Total amount of therapeutic agent is limited 0 𝑇 ℎ(𝑡) 𝑑𝑡≤𝑄, 𝑄=𝑐𝑜𝑛𝑠𝑡>0
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Problem Statement: System of Equations
𝑑𝐶 𝑡 𝑑𝑡 = 𝑟 1 𝐺 𝑔(𝑡) 𝑙𝑛 𝑎 𝑐 − 𝑙𝑛𝐶 𝑡 𝐶 𝑡 − 𝛾 1 𝐶 𝑡 − 𝑘 1 𝑓 ℎ 𝑡 𝐶 𝑡 𝑑𝑁 𝑡 𝑑𝑡 = 𝑟 2 𝐺 𝑔(𝑡) ln 𝑎 𝑛 − 𝑙𝑛𝑁 𝑡 𝑁 𝑡 − 𝛾 2 𝑁 𝑡 − 𝑘 2 𝑓 ℎ(𝑡) 𝑁 𝑡 −𝛽𝑁 𝑡 𝐶(𝑡) 𝑑𝑔 𝑡 𝑑𝑡 =𝛼 − 𝛾 3 𝑔 𝑡 − 𝜀 1 𝐶 𝑡 + 𝜀 2 𝑁 𝑡 𝑔(𝑡) 𝑑ℎ 𝑡 𝑑𝑡 =𝑔 𝑡 𝑢(𝑡)− 𝛾 4 ℎ 𝑡 − 𝜀 3 𝐶 𝑡 + 𝜀 4 𝑁 𝑡 ℎ(𝑡)
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Problem Statement: Therapeutic Strategy
Here, we denote: 𝑐 𝑡 =𝑙𝑛𝐶 𝑡 , 𝑛 𝑡 =𝑙𝑛𝑁 𝑡 𝑉={ 𝑐,𝑛 ∈ ℝ + 2 : 𝑐≤ 𝑐 , 𝑛≥ 𝑛 } The main goal is to find such therapeutic strategy (where control function 0≤𝑢 𝑡 ≤𝑀), that maximizes the viability time, i.e. , the time of staying in the safety region 𝑉 over all state trajectories to the system, under the condition: 0 𝑇 𝑢(𝑡) 𝑑𝑡≤𝑄, 𝑄>0
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Steady-state Analysis
An illustration of the fact that, even if 𝑐 ∗ , 𝑛 ∗ ∈ 𝑉 , the safety region can be left for some time. Here the parameters are taken as 𝛽= 10 −6 , 𝑘 1 =7, 𝑘 2 =1.45, 𝛿 1 =0.3, 𝛿 2 =0.45, the constant control is 𝑢 = 0.1, and three different initial coordinate pairs 𝑐 0 ; 𝑛 0 = 𝐼 1 , 𝐼 2 , 𝐼 3 are considered with fixed 𝑔 0 = 1, ℎ 0 = 0.
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Auxiliary Parameter Estimates
𝑘 1 is the therapy parameter: − 𝑘 1 𝑓 ℎ 𝐶 𝑡 𝑘 2 is damage parameter: − 𝑘 2 𝑓 ℎ 𝑁(𝑡) To kill 75% of cancer cells and preserve 50% of normal cells it is needed: 𝑘 1 𝑘 2 =3.79 If 𝑘 1 𝑘 2 =2 then we can to fill 75% of cancer cells, but preserve only 27% of normal cells
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Optimality Principal Let 𝑇 be a viable time. The optimal trajectory satisfies either 𝑐 𝑇 , 𝑛 𝑇 = 𝑐 , 𝑛 Or 𝑐 𝑇 = 𝑐 , 𝑛 𝑇 > 𝑛 The second case is possible only if 0 𝑇 𝑢(𝑡) 𝑑𝑡=𝑄
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Numerical Simulations
The results of numerical simulations are very sensitive to parameter 𝛽 which described the degree of competition between cancer and normal cells (−𝛽𝑁 𝑡 𝐶(𝑡)) Illustrations: the optimal process approximated by using the software package BOCOP for the parameter values 𝛽=10 −6 , 𝑄=0.14 (Case 1). The maximum viability time is 𝑇 1 = The integral constraint does not become active.
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Numerical Simulations
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Numerical Simulations
Illustrations: the optimal process approximated by using the software package BOCOP for the parameter values 𝛽=10 −6 , 𝑄=0.1 (Case 1I). The maximum viability time is 𝑇 2 = The integral constraint becomes active
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Numerical Simulations
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Numerical Simulations
Illustrations: the optimal process approximated by using the software package BOCOP for the parameter values 𝛽=2∗10 −6 , 𝑄=0.11 (Case IV). The maximum viability time is 𝑇 4 = The integral constraint becomes active
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Numerical Simulations
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Numerical Simulations
Illustrations: the optimal process approximated by using the software package BOCOP for the parameter values 𝛽=5∗10 −6 , 𝑄=0.07 (Case V). The maximum viability time is 𝑇 5 = The integral constraint does not become active
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Numerical Simulations
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Conclusion The result of numerical optimization shows the good agreement with the optimality principles Competition coefficient β plays role of the bifurcation parameter Significant characteristic of the model is ratio 𝑘 1 / 𝑘 2 between therapy and damage coefficient In biomedical practice the therapy and damage function (depending of drug concentration) are not precisely known
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References E. Afenya, C. Calderon, A brief look at a normal cell decline and inhibition in acute leukemia, Cancer Detection and Prevention 20 (3) (1996) K. Swanson, Mathematical modeling of the growth and control of tumors, Ph.D. thesis, University of Washington (1999) N. Stepanova, Course of the immune reaction during the development of a malignant tumour, Biophysics 24 (1980) H. Schattler, U. Ledzewicz, Optimal Control for Mathematical Models of Cancer Therapies: An Application of Geometric Methods, In Interdisciplinary Applied Mathematics, Vol. 42, Springer-Verlag, New York, 2015. A. Bratus, E. Fimmel, Y. Todorov, et al., On strategies on mathematical model for leukemia therapy, Nonlinear Analysis: Real World Applications 13 (3) (2012)
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References N. Komarova, D. Wodarz, Targeted Cancer Treatment in Silico: Small Molecule Inhibitors and Oncolytic Viruses, Birkhauser, 2014. A. Bratus, S. Zaichik, Smooth solutions of the Hamilton-Jacobi-Bellman equation in a mathematical model of optimal treatment of viral infections, Di. Equat. 46 (11) (2010) A. Bratus, Y. Todorov, I. Yegorov, et al., Solution of the feedback control problem in a mathematical model of leukaemia therapy, J. Opt. Theor. Appl. 159 (2013) A. Bratus, S. Kovalenko, E. Fimmel, On viable therapy strategy for a mathematical spatial cancer model describing the dynamics of malignant and healthy cells, Math. Biosc. Eng. 12 (1) (2015) 1-21. A. Bratus, I. Yegorov, D. Yurchenko, Dynamic mathematical models of therapy processes against glioma and leukemia under stochastic uncertainties, Meccanica dei Materiali e delle Strutture VI (1) (2016)
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