Review

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Computational modeling in glioblastoma:

from the prediction of blood–brain barrier
permeability to the simulation of tumor
behavior
Ana Miranda1,2 , Tânia Cova3 , João Sousa1,2 , Carla Vitorino*,1,2 & Alberto Pais3
1
Pharmaceutical Technology Department, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de
Santa Comba, 3000-548 Coimbra, Portugal
2
Pharmacometrics Group of the Centre for Neurosciences & Cell Biology (CNC), University of Coimbra, Rua Larga, Faculty of
Medicine, Pólo 1, 1st floor, 3004-504 Coimbra, Portugal
3
Coimbra Chemistry Center, Department of Chemistry, University of Coimbra, Rua larga, 3004-535 Coimbra, Portugal
* Author for correspondence: Tel.: +351 239 488 400; csvitorino@ff.uc.pt

The integrated in silico–in vitro–in vivo approaches have fostered the development of new treatment
strategies for glioblastoma patients and improved diagnosis, establishing the bridge between biochem-
ical research and clinical practice. These approaches have provided new insights on the identification of
bioactive compounds and on the complex mechanisms underlying the interactions among glioblastoma
cells, and the tumor microenvironment. This review focuses on the key advances pertaining to computa-
tional modeling in glioblastoma, including predictive data on drug permeability across the blood–brain
barrier, tumor growth and treatment responses. Structure- and ligand-based methods have been widely
adopted, enabling the study of dynamic and evolutionary aspects of glioblastoma. Their potential ap-
plications as predictive tools and the advantages over other well-known methodologies are outlined.
Challenges regarding in silico approaches for predicting tumor properties are also discussed.

First draft submitted: 25 May 2017; Accepted for publication: 5 September 2017; Published online:
13 December 2017

Keywords: blood–brain barrier • cancer treatment • computational modeling • glioblastoma • ligand-based meth-
ods • structure-based methods

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, being associated with poor prognosis
and high rates of morbidity. Despite the progressive research and the efforts made to improve tumor treatment, the
median overall survival time for GBM patients remains only approximately 12–15 months [1–4]. Such efforts have
been focused on getting a comprehensive and thorough understanding of the molecular pathogenesis of GBM, and
dynamic interactions among GBM cells [1,5].
New modalities in biomedical research, encompassing in silico–in vitro–in vivo approaches, have arisen to improve
outcomes in patients with GBM [5]. Specifically, in silico models have been used to predict useful data for both in
vitro and in vivo studies, so as to complement the results obtained in clinical trials. In turn, in vivo models provide
feedback to in silico models for further developments and optimization [6]. This allows, for example, combining
biological data, such as cell-cycle related events and methylation status of the DNA repair gene MGMT with
chemo- and/or radiotherapy treatment responses [7].
Computational models have thus become a standard tool to mimic biological systems and to study cellular
phenomena in multidimensional approaches. Based on mathematical, physical and engineering concepts, these
models are able to provide molecular signatures (including genomics and proteomics), imaging data (magnetic
resonance images, microscopy imaging, among others) and clinical information [5,6,8,9]. Regarding brain tumors,
particularly GBM, systems-driven computational approaches have attracted increased attention, since they allow
to simulate and predict a set of complex phenomena: tumor cell kinetics and dynamics (including tumor growth

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Review Miranda, Cova, Sousa, Vitorino & Pais

patterns and invasion), angiogenesis, pharmacokinetic profiles of drugs and its permeability across the blood–brain
barrier (BBB), therapeutic responses, signaling pathways involved in drug resistance, among others [6,8,10,11].
To achieve such ambitious information through computational brain tumor models, different biocomplexity
scales in time and space must be integrated, in order to accurately address the tumor dynamics [5,10]. These in
silico multiscale tumor models are already enabling the analysis of tumor complexity at an atomic (length scales
of nm and time scales of ns), molecular (nm–μm/ns–s), microscopic (μm–mm/min–hour) and macroscopic
(mm–cm/day–year) level, depending on the purpose of the study. In the case of GBM models, different biological
spatial scales can be used to analyze the structure and dynamics of lipids, proteins and peptides, at the atomistic
level, point mutations and cell signaling mechanisms, at the molecular level, malignant transformation of healthy
cells, intratumor phenotypic heterogeneity, tumor microvasculature and microenvironment, at the microscopic or
tissue/multicellular level, and tumor size, shape, composition, as well as the extent of vascularization and invasion,
these latter at the macroscopic or organ level [10,12]. In practical terms, it is noteworthy that very few attempts have
been made to quantitatively establish a relationship between molecular and cellular scales in brain tumor models
so far [10].
In silico multiscale tumor models are thus quantitative models developed on the basis of a prior decision of some
parameters, including the modeling scale(s) under study, the established tumor boundary, and the evaluation of
level of complexity versus computational cost [10]. Moreover, the computational modeling of tumor behaviors is
possible through commonly used approaches, such as discrete (individual-based), continuum (population-based)
or hybrid techniques [5,10,12]. First, continuum models are useful to describe the extracellular matrix or the entire
tumor tissue as a continuum, therefore being suitable for modeling larger-scale volumetric tumor growth dynamics.
Changes in tumor cell density, spread of cancer cells into the surrounding tissues and cell substrate concentrations
(such as oxygen, nutrients and growth factors), are some of the processes analyzed through continuum models.
However, these models present low sensitivity to small fluctuations at the genetic and cellular levels. This limitation
may be critical if the purpose of the study is to evaluate tumor heterogeneity associated to cell properties or to
detect small changes responsible for significant variations in tumor behavior [5,10,12]. In turn, discrete models are
used to represent individual cells or cell clusters in space and time, applying a set of biological rules needed to study,
for example, cell–cell and cell–matrix interactions, genetic instability or carcinogenesis mechanisms. In spite of
these models providing information about the diversity of cellular and subcellular dynamical features, their major
drawback are related to the limited number of cells that can be modeled, mainly due to the large computational
cost [10,12]. Considering the hypercomplexity of cancer-related processes, multiscale hybrid (continuum-discrete)
models are becoming increasingly popular, especially in brain tumor modeling. These hybrid models have the
potential to integrate the benefits of both continuum and discrete descriptions [5,10,12].

In silico modeling of GBM

Computational (in silico) approaches have been developed to establish diagnostic and prognostic molecular patterns
and identify defective pathways involved in cancer mechanisms. These include data repositories, machine learning,
pattern recognition and similarity profiling, network analysis, structure–activity relations, pharmacophore mapping
and modeling of molecular scaffolds. Such methods have been widely used in the design and optimization of novel
drug-like molecules with improved affinity to specific targets, and in the scrutiny of absorption and distribution
mechanisms, toxicity and physicochemical features [12–14].
The in silico methods have been increasingly recognized as a valuable tool by the scientific community as a
low cost and less time-consuming alternative to assess and screen experimental data [6,10,15,16]. Nowadays, the
simulation of GBM in silico is already offering ways to explore a set of cancer dynamic processes at different scales,
being the selection of this scale a very important task. Several studies have focused on drug permeability across the
BBB, tumor growth, cellular signal transduction pathways, tumor microenvironment and therapeutic responses
phenomena [1,6,8,10,13]. The major challenges in the modeling of brain tumors include finding an appropriate
functional representation, defining the respective validation procedure and incorporate in that function various
relevant information from different techniques. Practical aspects, such as the definition of tumor boundaries, cannot
also be overlooked [9].

Ligand-based methods
Ligand-based methods have been mostly applied in computer-aided drug design, based on information of the
biological and physicochemical properties of compounds recognized to be adequate for the binding to the target

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of interest. Ligand-based virtual screening and quantitative structure–activity relationships (QSAR) modeling are
the commoner tools within this group of methods [13,17]. These use information relative to the conformation
and physicochemical properties of bound ligands, and also on the structure of the targets. The molecular features
responsible for the molecular activity are represented by adequate molecular descriptors. Ligand-based virtual
screening has been used in drug discovery based on comparative molecular similarity analysis of ligands. The
molecular descriptors enable to identify novel molecules with similar and optimized biochemical activity, when
compared with the already known active compound for a given transporter [13,18].
In simple terms, a QSAR algorithm defines the relation between the chemical descriptors and the biological
activity of the drug molecules, after a suitable functional form has been selected. Its parameters are established on
the basis of a learning set, and can be used to promote a virtual screen on putative new drugs. Such relationship can
be established using various chemometrics tools including regression- (e.g., multiple linear regression and partial
least squares) and classification-based methods (e.g., linear discriminant and cluster analysis), aiming at developing
models for quantitative and graded response data, respectively. In cases of high-dimensional and complex chemical
data, containing nonlinear relationships with the response properties, other machine-learning tools, such as artificial
neural network and support vector machine are also used in developing predictive models. It should be noted that
an effective feature selection should also be carried out before building any statistical model, eliminating redundant
information and ensuring the use of relevant descriptors [11,15,19,20].

Mimicking the blood–brain barrier permeability

It is widely known that the BBB is a major ‘obstacle’ to deliver drugs to the brain. It strictly controls the brain
microenvironment by limiting the penetration of several therapeutic agents [20,21]. Several mathematical and
computational models have been successfully developed to simulate and predict the interaction of compounds with
the BBB interface [11]. Regarding neuromedicine, in silico research has shown potential to accelerate drug design
and discovery, as well as to predict the brain uptake and new insights on BBB transport mechanisms [16]. The BBB
permeability can be quantified experimentally by comparing the drug concentration in the brain and blood [15].
However, this involves the overspending of resources associated to in vivo experiments and becomes impractical
to be used for drug screening at larger scales. As an alternative, the BBB permeability of drugs has been predicted
resorting to in silico approaches based on several physicochemical descriptors of such compounds. These include
lipophilicity (as calculated from log P), topological polar surface area, water-accessible volume, hydrogen bonds,
rotatable bonds, molecular weight, ionization potential, charge, among many others [15,20,22].
A detailed analysis of the binding specificities of BBB transporters allows selecting the molecules with optimal
permeability [13,22]. Two permeability indices, log [brain]/[blood] (log BB) and log permeability-surface area (log
PS), are usually retrieved from experimental data of either in vitro or in vivo studies [16,19,23]. Thus, modeling
algorithms have evolved to quantitatively describe the brain penetration, surpassing the old and qualitative fashion
approaches, based on a limited compound classification as either BBB+ (a compound that crosses the BBB and
attain central nervous system) or BBB− (a compound that does not cross the BBB and does not attain central
nervous system). For further details see references [13,15,22,23].
Most of the in silico predictions use QSAR-like models [11,15,19,20]. For example, Bujak et al. [24] demonstrated
the benefits of using molecular energy-related descriptors, such as isolated atomic energy, in combination with other
common descriptors (e.g., molecular mass, log BB and log P), for predicting the BBB permeability of more than 70
chemical compounds, as potential drug candidates. For that, a QSAR model defined by a multiple linear regression
equation and subjected to both internal and external validation approaches was developed, and successfully applied
in a forensics-related case. In other study, a hybrid QSAR strategy, encompassing both k-Nearest Neighbors and
support vector machine methods, allowed to predict the BBB permeability of lead compounds at early stages of
drug development. In fact, results suggested that it is possible to obtain a more concise information of the possible
mechanisms underlying the BBB penetration of compounds, when descriptors derived from 2D molecular topology
are used. Some specific descriptors, such as the E-state index and van der Waals surface area, were found as possible
indicators for both passive diffusion ability and binding affinity of compounds with efflux transporters [25]. Actually,
it also became possible to predict the permeability of molecules that cross the barrier through either passive diffusion
or active transport (for details see references [13,15,22,23]). It is well known that small molecules may cross the BBB via
passive diffusion, while larger molecules (e.g., insulin, chemotherapeutic drugs) require more complex mechanisms
of transport associated to multidimensional factors as illustrated in Figure 1. The development of computational
methods capable to predict the BBB permeability of compounds, considering the specific type of transport, is now

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Active efflux
transport Paracellular
transport Adsorptive-
mediated
transport

Blood
+

+
Brain

Receptor-
Carrier-mediated mediated
Figure 1. Schematic representation
Passive transport transport
of the standard mechanisms of
diffusion drugs passing the blood–brain
barrier.

a major challenge. Within this scope, more comprehensive strategies based on drug clinical phenotypes have been
proposed to overcome the limitations of chemical feature-based methods [15].

Structure-based methods
Structure-based virtual screening (SBVS), molecular docking and molecular dynamics (MD) simulations are the
standard methods for molecular recognition events, and include the study of molecular interactions, induced
conformational changes and energetics of binding. Molecular docking provides a direct interaction study between
ligand and selected targeted binding sites, helping in establishing the recognition process. MD, in turn, samples
equilibrium situations compatible with the imposed temperature, for portions of the system and overall duration
imposed a priori. The latter allows estimating relevant properties of the interaction components, and respective
trends and behavior. Further detail is thus usually provided in MD, at a larger computational cost [13].

BBB features: integrity & permeability

Molecular docking-based methods have been successfully used to determine BBB transporters-dependent perme-
ability, by docking the compounds in study to efflux/influx protein models [19]. For instance, substrates or inhibitors
for the ATP-dependent efflux transporter P-gp in the BBB have been identified through models constructed based
on the structure of P-gp mouse homolog. Other BBB active transporters, such as LAT-1 and GLUT1, have also
been considered for molecular docking [16,23,26,27]. Schlessinger et al. [27] selected some small-molecule ligands for
LAT-1 (3,5-diiodo-L-tyrosine, 3-iodo-L-tyrosine, fenclonine, and the anticancer agent acivicin) by SBVS, when
modeled the LAT-1. The high affinity of acivicin with LAT-1 and the consequent active transport across the BBB
was later confirmed in clinical trials, with acivicin inducing significant toxicity due to high concentrations in the
brain. QSAR modeling and molecular docking strategies are commonly employed as drug discovery computational
techniques, integrated in a structure-based drug design instead of a ligand-based drug design [13,20]. Novel molecules
prone to bind to the active sites of transporters can be tested in two sequential phases. First, a candidate molecule
(lead compound) is selected by SBVS from large collections of compounds. This is governed by a previous docking
into the chosen BBB target binding site, so as to evaluate the molecular interactions and favorable structures.
The next step is to perform docking studies to predict optimal conformation of the leader molecule in the BBB
transporter active site, through chemical modifications, in order to optimize its BBB permeability. The molecular
docking approach has become a key tool in drug discovery over time by the identification and fine-tuning of a lead
compound [13,20].
More recently, MD simulations of the BBB crossing phenomena have been performed, taking advantage of
their stochastic and random behavior to predict some molecular processes, at an atomistic level, involved in
membrane permeability [19,21]. MD models are useful to assess the physicochemical parameters that have impact

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on both passive diffusion and active transport mechanisms across the BBB [28]. The models of bilayer membranes
for mimicking BBB are composed of phosphatidylcholine, the major lipid type within cellular membranes. The
dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine
(DMPC) and palmitoyloleoylphosphatidylcholine (POPC) have been employed as the most common membranes
models [19,21,22,29–31].
Most studies on this subject have already been summarized in a recent review (see reference [32]). Further examples
can be found in the references [14,19,21,29,30,33–36]. Recently, the DOPC bilayer system was used to compute effective
membrane permeability (Peff ) for a set of small compounds [18]. Free-energy calculations based on potential of
mean force (PMF) [31] have also been used to provide the bridge between the underlying free energy patterns
and the mechanistic details involved in the BBB permeability of the compounds [19,20]. The atomistic models
for the BBB have consisted of two membrane types, POPC and DMPC. The PMF of single neuroactive drugs,
that cross the BBB (denoted as BBB+ ) is typically lower within the membrane, in relation to those of BBB− . A
fundamental aspect to be understood is the precise manner in which the model drug-like molecules interact with
the BBB, and the respective effect on the membrane permeability. In this type of systems, the PMF represents
free energy as a function of some reaction/interaction coordinate that varies along the permeation pathway. PMF
calculations ‘force’ the sampling in high energy regions of potential energy, thus allowing estimating the free energy
barrier for the molecules crossing the BBB (Figure 2). This can be extracted using common strategies, such as
umbrella sampling simulations, which allows estimating the free energy (G) of the permeation process. The value
of G is simply the difference between the highest and lowest values of the PMF curve (see Figure 2), as long as
the values of the PMF converge to a stable value at large center-of-mass distance [31,32]. Specifically, independent
simulations are performed in each of the imposed regions of the reaction coordinate (Figure 2, bottom), using a
bias potential to constrain the simulations to adjacent windows. Such initial configurations are generated, each
corresponding to a location wherein the molecule of interest is harmonically restrained at decreasing or increasing
center-of-mass distance from the center of the bilayer, using an umbrella biasing potential. This restraint allows the
targeted molecule to sample the configurational space in a defined region along a reaction coordinate. Then, the
biased system (Figure 2, middle) will sample configurations close to a defined position (z0) even when these would
not be sampled in the unbiased system. The mean force, as a function of position, is calculated in each window,
and potentials are derived for each window using an unbiasing procedure. Statistical techniques, such as weighted
histogram analysis method, are used to remove the umbrella bias and combine the local distributions, allowing the
free energy to be computed (Figure 2, top).
The diffusion coefficients have been combined with the free energy profile to estimate the Peff for the compounds.
The relative values of the permeability are then correlated to the logBB and logPS values, experimentally determined,
revealing the great potential of in silico models to accurately predict the passive permeation of the compounds
through the BBB [19].
In other studies, MD simulations have elucidated relevant aspects of the functional dynamics of BBB-located
efflux and influx transporters. Adenosine triphosphate-binding cassette transporters have been analyzed through
atomistic simulations, since they are closely linked to multidrug resistance efflux mechanisms [22]. Another example
is given in a study of the ability of insulin-coated gold nanoparticles to cross a POPC membrane. Insulin receptors
typically found in the BBB endothelial cells were inserted into the POPC membrane, so as to mimic a type of BBB
active transport. It was possible to compute the force required for the nanoparticles to cross the BBB, as well as the
diffusion coefficient under forced conditions [21]. MD simulations may also have other applications in relation to
the BBB, such as membrane integrity studies. These simulations were employed to modulate tight junctions (TJs)
from the BBB combined with a nanobubble, in order to study the effect of bubble collapse on the integrity of
the TJ. Claudin-15 proteins were inserted in a cylindrical pore created in the center of a DPPC model membrane
to mimic the TJs. Serious damage in the DPPC-TJ model was reported after nanobubble implosions (cavitation
effect) induced by the shock waves. The damage observed in the BBB suggests that microbubble-assisted ultrasound
can be a useful technique for drug delivery to the brain [30]. These and other examples of MD simulations, aimed
to study both the integrity and permeability of the BBB, can be found in Table 1.

Assessing system response

In silico docking experiments and MD studies can afford information on the signaling pathways involved in GBM,
and the therapeutic effects of novel compounds when bound to receptors which are usually overexpressed in this type
of tumor. The major oncogenic pathways, such as the normal and mutant EGFR mediated PI3K signaling, as well

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PMF

Free energy

0
Distance from bilayer center

Constructing the PMF

Z0
Simulation Histogram Part of PMF
window

Reaction coordinate

Lipid Drug-like
bilayer molecule

Umbrella
sampling

Figure 2. Schematic representation of the umbrella sampling procedure applied to a system described by the
pathway for the permeation of a model drug through a lipid bilayer.

as the MAPK signaling, have been computationally explored [38,39]. A mathematical model of signaling pathways
in GBM was developed to describe the expression levels of certain proteins of these pathways, in addition to the
study of the inhibitory effect of diallyl disulfide (DADS) against the kinases, by docking DADS with PI3K, ERK
and mutant EGFRvIII. The results supported the inhibitory effect of DADS on kinases at millimolar range [39].
Additionally, comparative docking studies with 44 compounds of interest against 3D structures of three selected

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Table 1. Summary of the main molecular dynamics simulations and related contributions for the blood–brain
barrier/glioblastoma multiforme models.
Membrane Simulation method Keywords of the study Ref.
model
DPOC MD simulations BBB permeability; MD simulation; density profiles; diffusion coefficients; umbrella [19]
GROMACS software sampling; PMF free-energy profiles; Peff values; logBB values; logPS values
gromos53a6 force field
DMPC MD simulations BBB permeability; magnetic gradient; chemical functionalization; MD simulation; [36]
NAMD2 software forces balance (molecular bonds and nonspecific interactions); electrostatic
CHARMM27 force field potential map; MSD; snapshots
POPC Steered MD simulations BBB permeability; steered MD simulation; interaction force profiles; diffusion [21]
SPARTAN software coefficient; insulin receptor ectodomain (protein data bank); VMD
DPPC CG simulations BBB integrity; shock wave impulse; CG and MD simulations; cavitation effect; [30]
MARTINI force field claudins-15 (typical TJ proteins); RMSD curves
MD simulations
GROMACS software
POPC Steered MD simulations BBB permeability; steered MD simulation; gradient magnetic field; interaction force [14]
NAMD software profiles; VMD; video output frequency
CHARMM27 All-Atoms force field
DPPC, MD simulations BBB permeability; MD simulation; QM methods; free energies of solvation; [29]
DPHYPC, Gaussian 09 package molecular volumes; atomic electrostatic charges; dipole moments; hydrogen bond
DLPC, donors/acceptors; cavity effects in water; logPS values; logBB values
DOPSE, POPC
POPC MD simulations Interactions with BBB; PMF free-energy profiles; umbrella sampling; RDF; [33]
GROMACS software trajectories inspection with VMD; pKa changes
OPLS all-atom force field
DMPC MD simulations BBB: membrane-interaction QSAR model; logBB values; intramolecular [34]
Molsim package physicochemical properties; intermolecular solute-membrane interaction properties
MM2 force field
POPC MD simulations Interactions with BBB; VMD; RDF; noncovalent electrostatic interactions; hydrogen [35]
NAMD2 software bonds; electron density profile
CHARMM force field
POPC MD simulations BBB permeability; PMF free-energy profiles; umbrella sampling; deuterium ordem [37]
POPC:Chol United-atom force field parameter; area per lipid; bilayer thickness; hydrogen bonding; electrostatic
SpM:Chol potential; mass density profiles; lateral diffusion
BBB: Blood–brain barrier; CG: Coarse grained; Chol: Cholesterol; DLPC: Dilauroyl phosphocholine; DMPC: Dimyristoylphosphatidylcholine; DOPSE: 1,2 – dioleoyl phosphatidylser-
ine; DPHYPC: Diphytanoylphosphatidylcholine; DPOC: Palmitoyloleoylphosphatidylcholine; DPPC: Dipalmitoylphosphatidylcholine; logBB: Log [brain]/[blood]; logPS: Log
permeability-surface area; MD: Molecular dynamics; MSD: Mean square displacement; OPLS: Optimized potential for liquid simulation; Peff: Effective membrane permeabil-
ity; PMF: Potential of mean force; POPC: Palmitoyloleoylphosphatidylcholine; QM: Quantum mechanical; RDF: Radial distribution function; RMSD: Root-mean-square deviation;
SpM: Palmitoylated sphingomyelin; VMD: Visual molecular dynamics; QSAR: Quantitative structure–activity relationship.

targets of GBM, including EGFR, EGFRvIII and EphA2, were carried out. Following that, an MD simulation was
performed with the two most promising compounds (tetracenomycin D and chartreusin) and the three molecular
targets of GBM, in order to analyze the interactions between them and the respective stabilities. Tetracenomycin
D and chartreusin demonstrated higher binding affinity than the commercially available drugs, being considered
potential inhibitors for the treatment of GBM against the three selected targets [38].

Other methods
Predicting GBM growth & invasion
Several mathematical models have been proposed in evolutionary biology and oncology, providing, among other
aspects, the mechanistic details of cellular kinetics [40]. These models have been used in the context of GBM to predict
the evolution of tumor growth, and explore relevant aspects related to the tumor environment and the invasion into
surrounding tissues. The reaction diffusion-based GBM growth models were pioneered in 1989, and quickly became
a widely used approach [41–44]. These multiscale models are able to simulate, through partial differential equations,
glioma cell density changes, as a function of space and time [41–44]. For instance, a continuum 3D mathematical
model of avascular glioma growth was developed for simulating multiple cellular microenvironmental interactions,
spatial cell heterogeneity and phenotype differentiation. This consisted of four different glioma cell phenotypes
(hypoxic, hypoglycaemic, proliferative and necrotic) and a representation of the tumor environment, including the
host tissue and its components [43]. The model provided some predictive data based on the invasion, proliferation

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and the nutrients depletion rates, allowing to simulate different tumor evolution events and decisive prognosis of
glioma progression.
With the aim of exploring the interactions between the GBM and their microenvironment, such as the impact
of microglia on tumor invasion, a 3D mathematical and computational model was proposed. This allowed further
inspecting of the impact of glioma and microglial cells densities, and the concentration of several growth factors,
matrix proteins and other signaling molecules [41]. A dynamic 3D mathematical modeling system was also proposed
in order to evaluate the effect of chemical and hemodynamic changes in the early GBM growth process. Specifically,
hemodynamic and chemical microenvironment alterations, such as vessel diameter and permeability, oxygen level,
vascular endothelial growth and proteins’ prevalence, were investigated to explore the dynamics of the processes
related to co-option of pre-existing vessels, angiogenesis, glioma cell proliferation and tumor invasion. The important
role of the cell migration along host vessels in GBM research was clearly reinforced. The effect of additional features
in the model, including the cell migration and vessel redesigning, may improve the discrimination of GBM growth
from other solid tumors [42].

Predicting treatment effects

Bearing in mind the stochastic nature of the numerous biological processes involved at the different stages of cancer,
it seems clear that the use of equally stochastic techniques, such as Monte Carlo (MC) simulations, is clearly useful
in the field of cancer research [45]. Among the random phenomena that can be simulated in GBM using MC, there
are, for instance, those that allow predicting the response to treatment. A probabilistic MC base excision repair
model was developed in order to address the inhibitory effect of methoxyamine on the base excision repair pathway
kinetics [46]. Moreover, MC calculations have been employed in the simulation of radiation treatment of tumor
cell populations [47]. Also, 3D MC photon transport code was used to predict photon distribution and the rate
of drug release in the heterogeneous brain tissue, with the support of computed tomography images to identify
tissue boundaries of the brain. This optical simulation aimed to set the best irradiation conditions for targeted drug
release to the brain, not affecting healthy tissues and reducing treatment time [48]. Along the same lines, another
MC GBM model to quantitatively assess the current clinical target volume practices in GBM external radiotherapy
was reported. This MC GBM model consisted of a population of cells genetically heterogeneous, combined with
a strong hypoxic microenvironment, with the aim to analyze, for each cell, the oxygen status, radiation-absorbed
dose, radiosensitivity, and the tumor clonogen probability [47]. Finally, MC calculations were used to predict the
biological consequences of radiotherapy on GBM cells, by investigating complex damages in cellular DNA (both
single- and double-strand breaks) after radiation exposure [49].
Other mathematical models have been applied to study the effects of treatments in GBM cells. For example,
a model for GBM treatment, encompassing both surgery and radiotherapy, was developed to analyze the related
benefits and the effects of extending the surgical resection [50]. Also, a proliferation invasion model intended to
evaluate the added therapeutic value of bevacizumab combined to surgical resection with radiation therapy was
reported [51].

Conclusion & future perspective

The use of in silico techniques, complementary to in vitro and in vivo approaches, has gained wide recognition in
GBM research. Increasingly sophisticated computational models have emerged to facilitate the understanding of
the dynamic mechanisms involved both in GBM pathogenesis and treatment responses. In fact, predictive in silico
oncology is an evolving subject getting closer and closer to clinical application. The simulation and modeling of
relevant changes in tumor microenvironment and treatment represent a formidable challenge fostering an important
area within brain tumor research. Despite these advances, it is important to note that much work still needs to
be done in this area, in particular in the development of innovative and improved computational models that
enable the so-called translational research. In silico GBM modeling is thereby demanding, with biomedical and
computational researchers moving forward along multiple fronts. It is believed that coupling of spatiotemporal and
multidimensional models with clinical imaging will be part of daily clinical care, as key tool for GBM diagnosis
and personalized systems medicine.

Financial & competing interests disclosure

The authors acknowledge the Fundação para a Ciência e a Tecnologia (FCT), Portuguese Agency for Scientific Research, for financial
support through the Research Project no. 016648 (Ref. POCI-01-0145-FEDER-016648), the project PEst-UID/NEU/04539/2013,

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 Computational modeling in glioblastoma Review

Executive summary
r Glioblastoma multiforme (GBM) remains one of the most aggressive cancers, still lacking effective treatment.
r Computational methods have provided new insights on cancer, gaining wide recognition in the GBM research
along with in vitro and in vivo approaches.
r GBM in silico models have brought new opportunities for exploring a set of cancer dynamic processes at different
biocomplexity scales in time and space.
r Blood–brain barrier permeability can be predicted from in silico models.
r Simulation of tumor growth and therapeutic responses is increasingly feasible.
r Predictive in silico oncology is getting closer to clinical application, now requiring innovative and improved
computational models for translational medicine.
r In a future perspective, spatiotemporal and multidimensional models combined with clinical imaging may prove
to be a valuable integrative tool for GBM diagnosis and personalized systems medicine.

and COMPETE (Ref. POCI-01–0145-FEDER-007440). The Coimbra Chemistry Centre is also supported by FCT through the
Project no. 007630 UID/QUI/00313/2013, co-funded by COMPETE2020-UE. T Cova acknowledges the PhD research Grant
SFRH/BD/95459/2013, assigned by FCT. The authors have no other relevant affiliations or financial involvement with any or-
ganization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

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