Citation: Filippo Cacace, Valerio Cusimano, Alfredo Germani, Pasquale Palumbo, Federico Papa. Closed-loop control of tumor growth by means of anti-angiogenic administration[J]. Mathematical Biosciences and Engineering, 2018, 15(4): 827-839. doi: 10.3934/mbe.2018037
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Anti-angiogenic therapies are cancer treatments, proposed at first by Folkman [13] in the early seventies, consolidated along the nineties by several discoveries on the main principles regulating tumor angiogenesis [20] and widely debated in several theoretical and experimental studies throughout the last decade. Anti-angiogenic treatments aim at inhibiting the development of the vascular network necessary to support tumor growth during the vascular phase, so providing a way to control the heterogeneous and growth-unconstrained tumor population throughout the control of the homogeneous and growth-constrained population of endothelial cells [7,12]. Tumors have the capability to develop resistance to the conventional chemotherapeutic drugs mainly because of the rapidity of tumor cells in evolving towards new resistant phenotypes. Due to the indirect action of the anti-angiogenic drugs, the outcome of the therapy should not be impaired by the capability of tumor cells to generate resistant phenotypic variants [16,17], and the effectiveness of anti-angiogenic treatments on the control and possible remission of experimental tumors has been demonstrated [17]. Moreover, anti-angiogenic therapies have limited side effects respect to the conventional chemotherapies and radiotherapies. Conventional chemotherapies may also have anti-angiogenic effects on the vascular network [1,18,19].
The scope of this note is to investigate and design a closed-loop model-based anti-angiogenic therapy. The adopted model refers to [14], where a quantitative model describing the growth of experimental tumors under the control of the vascular network is presented. In [14], Hahnfeldt and coworkers introduced the concept of the carrying capacity of the vasculature, i.e. the tumor volume potentially sustainable by the vasculature, in order to account for the vascular control on the tumor growth. As the carrying capacity is strictly dependent on the vasculature extension, its dynamics can be assumed to represent the dynamics of the vascular network. Moreover, the effect on the carrying capacity of stimulatory and inhibitory angiogenic signals produced by the tumor itself and of administered anti-angiogenic drugs are explicitly accounted by the model formulation. The paper represents one of the first attempts to model, with a minimal number of parameters, the interplay between the dynamics of the tumor volume and of the carrying capacity, with or without administration of anti-angiogenic drugs. In [14] the predictions of the model have also been successfully compared with experimental data on anti-angiogenically treated and untreated Lewis lung tumors in mice.
Besides experimental frameworks, the model proposed in [14] has been widely exploited in theoretical studies in order to predict the effectiveness of new anti-angiogenic therapies and some model extensions have also been proposed in the related scientific literature. In [8] some model modifications are proposed and conditions for the eradication of the tumor under a periodic anti-angiogenic treatment are provided. In [23,24] problems addressing the optimal scheduling of a given amount of angiogenic inhibitors are presented. Anti-angiogenic therapies are nowadays investigated for their use in combination with chemotherapy, within the framework of a multidrug cancer therapy, and the Hahnfeldt model is still a landmark to synthesize and validate both combined or pure anti-angiogenic drug therapies. In [11] the optimal scheduling problem of a combined radiotherapy and anti-angiogenic treatment is formulated by exploiting a suitable modified version of the original model. Further extensions are also proposed in [9], where the authors aim at describing the interplay between the populations of tumor cells and endothelial cells subject to a combined therapy of chemotherapeutic and anti-angiogenic drugs. In [10] an optimal scheduling problem for the combined chemotherapeutic/anti-angiogenic treatment is presented. The reader may refer also to the very recent [21], where a modified version of [14] accounting for multiple control delays related to pharmacodynamic/pharmacokinetic drug absorption is exploited, in order to investigate local controllability and optimal control on a finite treatment horizon utilizing anti-angiogenic therapy combined to chemotherapy. On the other hand, pure anti-angiogenic approaches are still investigated in the recent literature, like in [22,26], where optimal and robust control strategies are applied to the linearized version of [14].
By suitably exploiting the Hahnfeldt model [14], tumor volume reduction is here pursued according to a closed-loop, model-based approach, with the control strategy making use of the feedback linearization theory [15]. To this end only available tumor volume measurements are exploited, with the carrying capacity estimated by means of a state observer for nonlinear systems [4,6], and the regulator synthesized as a feedback from the observed state. As known, the purpose of anti-angiogenic treatment is to keep the tumor volume below a safe level and for this reason the closed-loop control law is designed to track a desired volume level smaller than the safety value, possibly starting from a high level situation.
Preliminary results have been presented in [5], where a continuous stream of measurements has been considered. Instead, in a realistic therapeutic setting, measurements are acquired at discrete sampling times. In order to comply with this issue without resorting to an approximate discretization scheme, we exploit recent developments in the theory of time-delay systems [2] where sampled measurements are modeled as continuous-time outputs affected by time-varying delays [25], according to which the continuous-discrete control problem can be reformulated as a continuous problem with delayed measurements. We pursue this approach to design the state observer for the tumor-growth control algorithm.
It is proven that the control scheme allows to set independently the control and the observer parameters, thanks to the structural properties of the tumor growth model that guarantee the separability of estimation and feedback control algorithms.
Simulations are carried out in order to mimic a real experimental framework on mice. These results seem extremely promising with respect to both the reduction of the tumor growth level and to the bound on the average drug administration, required to make feasible the proposed drug delivery therapy. More in details, simulations provide very good performances according to the measurements sampling intervals suggested by the experimental literature, and show a noticeable level of robustness against the observer initial estimate, as well as against the uncertainties affecting the model parameters.
The paper is organized as follows. The next section is devoted to detail the tumor growth mathematical model chosen to design the closed-loop control law, which is defined in Section 3, where the main results are provided. Simulations are reported in Section 4. Conclusions follow.
The model under investigation is a nonlinear model accounting for angiogenic stimulation and inhibition [14], and is given by the following Ordinary Differential Equations (ODE) system:
˙x1=−λx1ln(x1x2),˙x2=bx1−(μ+dx2/31)x2−cx2x3, | (1) |
where
Being the anti-angiogenic drug not directly administered in vein, a further compartment is considered to account for drug diffusion:
x3(t)=∫t0e−η(t−t′)u(t′)dt′, | (2) |
with
˙x1=−λx1ln(x1x2),˙x2=bx1−dx2/31x2−cx2x3,˙x3=−ηx3+u, | (3) |
where
We assume that the only available measurement, exploited to design the control law, is the size of the tumor, that is, the first component of the state vector
˙x=f(x)+g(x)u, | (4) |
yk=h(x(kT)),k=1,2,…, | (5) |
where
f(x)=[−λx1ln(x1x2)bx1−dx2/31x2−cx2x3−ηx3],g(x)=[001], | (6) |
h(x)=x1=Cbx,Cb=[1 0 0]. | (7) |
Without a control input (i.e. with
x1,ss=x2,ss=(b/d)32=ρ. | (8) |
The goal of the proposed control scheme is to design a feedback control law
x2=r,x3=b−dr2/3c,u=ηc(b−dr2/3). | (9) |
The aim of steering system (3) to the equilibrium (9) can be achieved by properly exploiting the output feedback linearization theory to synthesize a state-feedback control law and by using a state observer to provide an estimate of the state. Indeed, we do not have a complete knowledge of the state, but we assume to measure only the tumor size, i.e. the first component of
ˉh(x)=ln(x1), | (10) |
¯yδ(t)=ˉh(x(t−δ(t)))=ln(x1(t−δ(t)))=ln(yk),t∈[kT,(k+1)T) | (11) |
where the last equality is obtained from
Lgˉh(x)=LgLfˉh(x)=0, | (12) |
LgL2fˉh(x)=−λc≠0, | (13) |
where
Lfˉh=dˉhdxf,Ljfˉh=dfLj−1fˉhdxf,j=2,3,…. | (14) |
In order to define the observer-based control, we use a nonlinear change of coordinates based on the drift-observability map [6], which in our case is
z=Θ(x)=[ˉh(x)−ln(r)Lfˉh(x)L2fˉh(x)]=[ln(x1)−ln(r)−λlnx1x2λ2lnx1x2+bλx1x2−dλx2/31−cλx3], | (15) |
and we consider the hypotheses needed by the observer based on this map.
In [2] it has been proven that, if
u(t)=L3fˉh(ˆx)−Kcˆzλc,ˆz=Θ(ˆx), | (16) |
where
˙ˆx=f(ˆx)+g(ˆx)u(t)+JΘ(ˆx)−1e−βδ(t)Ko(¯yδ(t)−ˉh(ˆx(t−δ(t)))), | (17) |
provides a closed-loop system with the origin of the state space
Hypotheses
As for
[0,ρ]×[0,ρ]×[0,¯x3], | (18) |
where
Unfortunately, (18) cannot be chosen as the domain of interest
JΘ=dΘdx=[1x100−λx1λx20J31J32−cλ], | (19) |
where
J31(x)=λ(λx1+bx2−23dx1/31),J32(x)=−λ(bx1+λx2)x22. | (20) |
The properties needed by
D=[ε,ρ]×[ε,ρ]×[0,¯x3], | (21) |
where
L3fˉh(x)=λ2a(x)log(x1x2)−λ(bx1+x2x22)ξ(x)+cηλx3, | (22) |
with
a(x)=λ+bx1x2−23dx2/31,ξ(x)=bx1−dx231x2−cx2x3, | (23) |
and
In order to make
These additional hypotheses allow to state the following proposition.
Proposition 1. Consider system (4) with initial conditions complying with
D=[ε,ρ]×[ε,ρ]×[0,ˉu/η] | (24) |
is invariant in the interval
Proof. We have already stated that the domain
ⅰ)
ⅱ)
We will show that
−λx1(ˉt)ln(x1(ˉt)x2(ˉt))≤−λ˜x1(ˉt)ln(˜x1(ˉt)˜x2(ˉt))⟹x2(ˉt)≤˜x2(ˉt) | (25) |
which is a contradiction. Similarly, assume ⅱ) is true. That means:
bx1(ˉt)−dx2/31(ˉt)x2(ˉt)−cx2(ˉt)x3(ˉt)≤b˜x1(ˉt)−d˜x2/31(ˉt)˜x2(ˉt)−c˜x2(ˉt)˜x3(ˉt) | (26) |
and, after straightforward simplifications:
x1(ˉt)−˜x1(ˉt)x2/31(ˉt)−˜x2/31(ˉt)≤d˜x2(ˉt)b. | (27) |
Because of the sub-linear growth of
x1(ˉt)−˜x1(ˉt)x2/31(ˉt)−˜x2/31(ˉt)>1andd˜x2(ˉt)b<1. | (28) |
day | day | day | day | day |
0.192 | 5.85 | 0.00873 | 0.66 | 1.7 |
In summary, we can tune
This proves the invariance of
Due to the presence of input saturation the regulation theorem provided by [2] cannot be straightforwardly applied. Instead, the following result is provided.
Theorem 3.1. Consider the closed-loop system (4), (11), (16)-(17). Consider any positive
(ⅰ) it is possible to design the observer parameters
(ⅱ) it is possible to design the control gain
Proof. According to Proposition 1 there exists an upper bound
˙z(t)=Abz(t)+Bb((L3fˉh(Θ−1(z(t)))−cλu(t)), | (29) |
¯yδ(t)=Cbz(t−δ(t)), | (30) |
where
Ab=[010001000],Bb=[001]. | (31) |
Let us define the error
˙ez(t)=Abez(t)+Bb(L3fˉh(Θ−1(z(t)))−L3fˉh(Θ−1(ˆz(t))))−e−βδ(t)KoCbez(t−δ(t)). | (32) |
Denoting
‖L3fˉh(Θ−1(z(t)))−L3fˉh(Θ−1(ˆz(t)))‖≤γL‖z(t)−ˆz(t)‖=γL‖ez(t)‖. | (33) |
Eq. (32) does not contain
In closed loop, assuming
˙z=Abz+BbKcz−BbKcez+Bb(L3fˉh(Θ−1(z))−L3fˉh(Θ−1(z−ez))). | (34) |
If
˙ζ=(Ab+BbKc)ζ,ζ(0)=z(0). | (35) |
Hence, by choosing
Corollary 1. Hypothesis
The aim of the simulations reported in this section is to investigate the performance of the proposed algorithm on the ground of the experiments carried out in [14] on mice from which the following parameter values, constraints and initial conditions have been considered.
The desired level for the tumor size is fixed at
The value of the drug sensitivity
In the previous sections, it has been proved that the control scheme allows to set independently the control and the observer parameters, since the structure of the tumor growth model guarantees the separability of estimation and feedback control algorithms. This separation principle is followed in the setting of the observer-based control parameters.
In particular, we set the observer parameters
Ko=[1.20,0.44,0.05]T,β=1. | (36) |
The feedback control gain in (16) is
In order to evaluate the performance of the algorithm we define the following goals.
1.
2.
where the first goal ensures that the tumor size at the end of the treatment (day
Different simulation campaigns have been carried out according to different sampling times, which have been set at
In order to investigate the robustness of the algorithm efficiency for different model parameter settings, we simulated the tumor growth for a "population" of
Figure 2 shows the percentage of successes for the two proposed criteria for the population. It is apparent that the performances of the closed-loop control do not vary for sampling intervals in
Based on a mathematical model of tumor growth, this work proposes a closed-loop control law aiming at reducing the tumor volume. The model accounts for angiogenic stimulation and inhibition, and is one of the most adopted in the literature to simulate and predict the effects of anti-angiogenic drug delivery. Based on the feedback linearization theory, the control law makes use of an observer for nonlinear systems in order to design the model-based control by means of only available measurements. Theoretical results ensure that the control gain of the regulator can be set independently of the observer gain, thanks to the structural properties of the tumor growth model. Numerical simulations show the effectiveness of the control law in spite of a wide range of variation of the (not measured) carrying capacity as well as a noticeable level of robustness with the respect the uncertainties affecting the model parameters.
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day | day | day | day | day |
0.192 | 5.85 | 0.00873 | 0.66 | 1.7 |