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| de AndaJauregui and Hernandez´Lemus | PRECISION MEDICINE IN ONCOLOGY | VOL 1| NUMBER 1| 2016 | 9-23 9 www.eprecisionmed.com/pmo Received 8 July 2016; Revised 10 July 2016; Accepted 13 July 2016; Published 14 July 2016 *Corresponding author: [email protected], Tel.: +(52) 5553501970; Fax: +(52) 5553501990 THE PATH TO INTEGRATION IN COMPUTATIONAL ONCOLOGY Guillermo de AndaJauregui,´ Enrique Hernandez´Lemus* Computational Genomics Division, National Institute of Genomic Medicine, MEXICO´ ARTICLE _______________________________ HIGHLIGHTS This article provides a detail account of informatics and computational biology and its application in precision oncology. _______________________________ ABSTRACT The complexity of cancer makes precision medicine a most sought after goal. With each new technological advancement a plethora of data is gathered that moves us closer to it. However, integration of these efforts is still needed. Computational power is needed in order to process, manage, and integrate this information, in order to generate models that are useful in the clinical setting. The following is a review of the current computational oncology approaches and its challenges. KEY WORDS Cancer, Precision Medicine, Computational Oncology, Systems Biology, Integrative Genomics www.precision-medicine.in
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| de AndaJauregui and Hernandez´Lemus | PRECISION MEDICINE IN ONCOLOGY | VOL 1| NUMBER 1| 2016 | 9-23

9

www.eprecisionmed.com/pmo

Received 8 July 2016; Revised 10 July 2016; Accepted 13 July 2016; Published 14 July 2016

*Corresponding author: [email protected], Tel.: +(52) 5553501970; Fax: +(52) 5553501990

THE PATH TO INTEGRATION IN COMPUTATIONAL

ONCOLOGY

Guillermo de AndaJauregui,´ Enrique Hernandez´Lemus* Computational Genomics Division, National Institute of Genomic Medicine, MEXICO´

ARTICLE

_______________________________

HIGHLIGHTS

This article provides a detail account of informatics and

computational biology and its application in precision oncology.

_______________________________

ABSTRACT

The complexity of cancer makes precision medicine a most

sought after goal. With each new technological

advancement a plethora of data is gathered that moves us

closer to it. However, integration of these efforts is still

needed. Computational power is needed in order to process,

manage, and integrate this information, in order to generate

models that are useful in the clinical setting. The following is

a review of the current computational oncology approaches

and its challenges.

KEY WORDS

Cancer, Precision Medicine, Computational Oncology, Systems Biology, Integrative Genomics

www.precision-medicine.in

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INTRODUCTION The challenges for establishing precision medicine in oncology

In the years that follow the completion of the first draft of the human genome, high throughput

technologies gave rise to the idea that therapeutic options could be tailor made, based on the individual

characteristics of each patient at the genomic level. It took, however, more than a dozen years until the

Precision Medicine Initiative was able to brought into public attention the possibilities of incorporating

these technologies to current clinical settings [1]. Precision medicine (PM) –as it is presently understood–

should aim at being able to improve prediction, treatment, and outcomes.

Cancer, being an archetypal complex disease, is an obvious candidate for PM efforts due to its highly

heterogeneous, individual wise character. Cancer events involve multiple alterations at different levels:

molecular, tissue, and systemic. Each of these levels present its own challenges to study, many of them

related to inter-individual variability. PM in oncology intends to pave the way to the high level personalized

diagnostic, prognosis and treatment of cancers.

Of course, achieving success in this area is not an easy endeavour. Here we will consider some of the

challenges that contemporary research in oncology has to face and also the way in which several

disciplines have been developing strategies to cope with these. The key to success, in our opinion, is

integration of the strengths and capabilities of all the different approaches.

Genetic and environmental factors in cancer

The genetic contribution to cancer has been known for a long time. Since the discovery of the role of

oncogenes and tumor suppressors in the development of cancer [2–5], many genetic alterations have

been identified in different neoplasms [6], with genomic instability being now considered a hallmark of

cancer [7, 41]. Epigenetic effects in cancer [8–10] add another layer of complexity to the study of the

disease; however, the use of genetic information has led to success stories in both the diagnostic [11] and

treatment [12, 13] areas. Genetic cancer risk assessment and its use for therapeutic decision making is

also steadily gaining traction [14–18].

The contribution of environmental factors to carcinogenesis has also been known for a long time now [19–

23]. Gene-environment interactions are involved in the susceptibility to carcinogenic effects [24–27] and

have been a sought after subject of study [28–31]. In a similar fashion, genetic variants are associated to

differences in therapeutic susceptibility [32–35], again having an impact in clinical decision making [36–

39]. It is precisely this complex interplay between genomic susceptibility traits and environmental factors

which lies behind the poor results obtained by straightforward approaches to treat cancer. At the heart of

these interactions is the emergence of new phenomena giving malignant tumors a rather unpredictable

character.

Emerging factors in cancer

The study of individual factors in cancer has gradually given way to studies beyond the single molecule

level. Cancer has indeed been characterized as a pathway based disease [40, 41], with pathological

alterations being associated to deregulation in groups of molecules acting together. This approach has

been useful in bridging molecular data with functional information and clinical applications [42–46]. In a

similar way, integration of multiple molecular data types has led to increased efforts in studying the major

role that metabolic deregulation has in cancer. While the idea of energetic deregulation in cancer is not

new, dating back to Warburg [47], there is a renewed interest in metabolic phenomena in order to

understand the disease and perhaps, as a source of novel therapeutic targets [48–50].

Cancer is a molecular disease. However, it is now known that not only intracellular molecular deregulations

are involved in the disease, but a complex set of dynamic interactions between tumor cells and also

between the tumor and its surrounding microenvironment [51]. Cells of the immune system, adipocytes,

fibroblasts, vascular endothelial cells, among others with different tumor cells [52], include cancer stem

cells [53, 54]. Nowadays we recognize the need to understand not only the nature of tumors themselves,

but also their interplay with other cells.

The challenging path from knowledge to precision medicine, and the role of computational biology

We have witnessed a shift in the understanding of neoplastic diseases. The challenge now lies in being

able to incorporate each new finding in an intelligent, and most importantly, useful manner in order to

complete the much desired bench-to-bed goal of translational medicine. Computational oncology must

play two roles in order to accomplish this goal: To help collect, process, and compile the vast quantities of

data; and to develop and implement new models that combine the available information and eventually

become useful in the clinical decision making process.

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What follows is a brief description of the state of computational oncology, in the context of systems

biology. The two roles of computational oncology today are described, both as a data managing tool and as

a tool for modelling. We discuss the two main avenues for these research lines: the data-driven,

mathematical oncology approach, and the physical oncology approach. We present integrative frameworks

and current computational tools available, and finally we elaborate on what are the current areas in need

for further development of the discipline.

The systems biology paradigm

The Systems biology paradigm considers that complex phenomena behind the functions of biological

systems are the result of interactions between different constituting elements [55, 56]. Systems biology

attempts thus, to understand biological mechanisms behind phenotypes using large scale data and

mathematical models that use said data [57]. Cancer can be thought of as a systems biology disease [58,

59]. Nonlinear interactions between the many elements that are altered in cancer may drive the diseased

phenotype [60, 61]. The systems biology paradigm is useful then, in bringing together information in order

to generate both descriptive and predictive models [62].

Model generation is central to systems biology [63]. Biological, systems level models provide new insights

in the biological phenomena [64] something that is extremely important for oncology research. These

insights are useful in the generation of new hypotheses that may drive experimental research [65].

Furthermore, the contribution of systems biology must be understood as iterative [66]: models are

constructed based on data available, generating new hypotheses to be tested; new experiments are used

to refine the model, generating new hypotheses to be retested and so on.

The goals for the integrative, systems biology study of cancer should be directed at generating new models

regarding diagnostic and therapeutic choices, in order to gain improvements in prognosis, diagnostics and

ultimately therapeutics [67]. In order to do so, it is necessary to a) manage omics level data and b)

implement appropriate models based mathematical and physical principles using said data. It is evident

that for this, the use of computational approaches is mandatory.

COMPUTATIONAL ONCOLOGY Computational oncology is the study of cancer with computer-implemented tools from the quantitative

sciences [68]. As we have previously discussed, there are two main computational oncology branches as it

currently stands: first, the one related with processing, storage, retrieval and analysis of data generated

with analytical technologies; and second, the development of descriptive and predictive models that

incorporate said data, and are able to drive experimental research by generating new questions. More

importantly, computational oncology develops applications in the clinical setting in order to improve

diagnosis, treatment selection and prognosis.

In a similar fashion, computational oncology can be roughly divided on the basis of the disciplines from

which its applications are derived: Mathematical oncology originates in the mathematical and

computational sciences. It is cantered on the development and implementation of algorithms that enable

the analysis and management of biological data. Physical oncology comes from the application of ideas

derived from physical models to oncology problems.

Overlap between approaches exists, as this division is mostly descriptive, and in many cases the use of

language is more defined by previous training and self identification. Nonetheless, let us use this simple

classification in order to further discuss current uses of computational methods in oncology [Figure 1].

Mathematical Oncology

Mathematical oncology can be thought of as the use of mathematical techniques in order to extract

information from omics level datasets. Sufficient (that is, large) computational resources are needed in

order to be able to manage this data [69]. Some applications of mathematical oncology include database

management (that is, storage and retrieval of data), data processing, and data analysis. Let us examine

some of these applications in more detail.

Database management

Current large scale research deposits the data generated in readily accessible databases, with a rapid

growth in the number of databases and their sizes [70]. Several databases specialized in oncological data

exist, both from general studies (TCGA [71], COSMIC [72]) as well as related to particular types of cancer

(for instance, the METABRIC database [73]). Public repositories of experimental data, such as the Gene

Expression Omnibus and ArrayExpress [74] for microarray data are also largely used by researchers.

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As applications continue to be developed, the use of these platforms will be more common in the clinical

setting.

As technologies keep evolving, a major concern is the size of data. The difference in size between RNAseq

data and microarray data, for instance, is about an order of magnitude. Incorporating experimental data

from other levels of description (proteomics, metabolomics) directly increases the size of data. IT

requirements in the clinical setting shall then move forward to either a) the acquisition of large storage

media or b) the implementation of cloud-based storage, with dedicated infrastructure to rapidly and

efficiently access data.

Fig: 1. The roles of computational oncology. Analytical technologies generate large amounts of data that can only be

manipulated through information technologies. The development of tools for the processing, storage, retrieval and data analysis is one branch of computational oncology. Computational models can be developed, based on mathematical or physical principles, that uses said data in order to describe or predict the pathology. These models can be used to guide new highthroughput research. Finally, both data and models can be integrated into the clinical setting by using computational platforms. …………………………………………………………………………………………………………………………………………………

Imaging data processing and analysis

Imaging data has been for long, an important part of comprehensive cancer management, with a role in

screening, diagnosis, treatment selection and follow-up [75–77]. The traditional approach of expert

clinicians examining individual images is time consuming, and limited by the availability of qualified

professionals. Computer aided detection (CAD) techniques take advantage of image processing and

machine learning algorithms in order to assist said clinicians in data interpretation [78].

Computer aided interpretation of imaging data is currently used, for instance, in breast cancer screening

[79]. Routine mammography is used for breast cancer screening: in the United States, biennial screening

mammography is recommended for women age 50 to 74 years [80]. Studies have found evidence of

benefits in the use of CAD technologies, leading to increased diagnostic sensitivity [81–83]. A recent study

shows that the use of CAD for screening mammography increases the rate of detection of ductal

carcinoma in situ and early stage invasive cancer; however, it also shows an increased risk in false

positives [84]. The role of CAD for breast cancer screening has detractors, for instance [85]; however, the

authors of said work do consider that current limitations in CAD may be overcome with further research,

and describe the potential of CAD as ”limitless” [86]. Complementation between the use of new

technologies and the development of proper computational algorithms is needed in order to advance their

clinical relevance. Development of said algorithms is currently a productive area of research [87– 91]. Sequence data

Next generation sequencing (NGS) is expected to revolutionize the clinical setting [92, 93], allowing the

simultaneous determination of any genetic variant related to disease. Cancer is a disease that naturally

benefits from such approach, allowing to move away from the reductionist approach that former

technological limitations imposed [94] [Figure-2]. Currently, the main practical limitation for NGS in the

clinical setting is the cost. However, as the technology becomes more accessible, so will its uses [95, 96].

NGS has particular bioinformatics requirements. These have been described as primary, secondary and

tertiary analysis [97]. In primary analysis, instrument signals are processed in order to generate a

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sequence (for instance, a FASTQ file). In secondary analysis, a comparison with a reference sequence is

made. Finally, tertiary analysis involves the contextualization of variant information in order to enhance

clinical decision making.

NGS methodologies have been used in order to identify potentially pathogenic variants in patients [98,

99]. A goal is to be able to use NGS information to identify genomic biomarkers [100]. There have been

successful efforts in this regard, with pipelines that are able to identify potentially actionable alterations

[101–103]. The identification of useful, reproducible genomic biomarkers poses a considerable technical

feat [104]. It also presents computational challenges: Biomarker reproducibility for instance, is highly

sensible to the particular processing pipeline. Furthermore, algorithms do not always take into account the

intra-tumor heterogeneity present in cancer. Data analysis pipelines should be improved to take into

account these factors in order to have better clinical value [105].

Fig: 2. Computational applications in the analysis of Next Generation Sequencing data. By its very nature, the analysis

of data generated by NGS technologies can only be achieved through the use of computational tools. The processing and storage of raw NGS data requires considerable computational resources. Later, NGS analysis pipelines need to incorporate algorithms for sequence alignment, variant calling and finally, association of sequence data to known biological functions. …………………………………………………………………………………………………………………………………………………

As with other genomic data, the functional annotation of identified biomarkers, and its public sharing, is

vital. Again, the development of databases [106] will allow clinicians the ability to work with this

information. Meanwhile, data oriented scientists may use the information and implement computer based

approaches (such as data mining) to identify new biomarkers [107], an example of the feedback expected

in the development of precision medicine.

An important consideration for the use of these technologies is the need of validation for the clinical

setting [108]. Current guidelines stress the importance not only of platform validation, but also of the

validation of bioinformatics pipelines used for data analysis [109]. Identifying driver and passenger genes

A current problem in cancer genomics is the identification of driver mutations from passenger mutations,

that is, to identify a mutation that is causally implicated in oncogenesis from one that does not confer

clonal growth advantages [110]. For this, computational oncology approaches are necessary, and

constitute indeed a central area of research. Discerning between driver and passenger status usually

takes into account a) mutation frequency, b) mutual exclusivity of mutations between gene sets, or c)

information derived from pathway or other biological network annotation [111, 112].

Development and refinement of the computational strategies to identify driver from passenger genes is

ongoing [113]. In [114], a framework based on network enrichment analysis is proposed, able to properly

identify driver genes in gliobastoma and ovarian carcinoma data. In [115] evolutionary population dynamic

models are used in order to find driver genes in colorectal tumors. Meanwhile, [112] uses a methodology

capable of identifying driver genes with low mutational frequency due to epistatic interactions.

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Expression data

Gene expression data has notably impacted cancer research. Microarray, and more recently, RNAseq data

have been thoroughly used in order to profile the expression of several oncological diseases [116–124].

Evidently, the analysis of these high throughput technologies requires suitable bioinformatics techniques

able to go from raw experimental data all the way to expression quantification. Computational pipelines

suitable for specific technologies are available [125, 126].

Gene expression patterns associated to disease manifestations have been codified into gene signatures.

These have been extensively used in the characterization of neoplastic diseases [127–131]. Collections of

these signatures are available, for instance in the MSIGdb and geneSigdb databases [132]. Gene

signatures are increasingly being implemented as clinical indicators of drug susceptibility [133–135].

Another common use of molecular signatures is as prognostic tools. There is evidence that a expression

signatures can be linked to clinical outcome [136]. However, there exists a degree of controversy

regarding their actual usefulness in the clinic, particularly whether there is a unique signature with

predictive power [137–139]. Nonetheless, commercial applications of gene signatures for the clinical

setting are currently available [140]. Computational oncologists have two roles in this regard: first, using

robust informatical methods to identify the validity of signatures in the research setting; and second, to

implement adequate computational platforms in order to use gene signature profiling in the context of

molecular testing [141].

A closely related subject and a major triumph of mathematical oncology is the identification, using data

driven approaches, of breast cancer molecular subtypes. Molecular subtypes are different manifestations

of a disease, with particular clinical and pathological characteristics, that can be identified based on gene

expression profiles. Molecular subtypes were first identified in breast cancer [142–144]. Soon, PAM50, a

molecular classification strategy (based on nearest shrunken centroids [145]) was developed in order to

classify samples [146]. Commercial applications [147] make this classification strategy widely available,

with validated, predictive clinical value [148, 149]. Following the initial success of breast cancer sub-

typification, molecular subtypes have been identified for other cancers [150, 151]

Finally, transcriptional networks can be inferred from whole genome expression experiments [60, 152].

These networks provide a data driven model of relationships between genes based on the statistic relation

between them. Transcriptional networks can be as simple as co-expression networks (ie. Spearman

correlations) or use more sophisticated, information theoretical measures such as mutual information (for

instance, the ARACNE algorithm [153]).

Physical Oncology Physics has a long standing relationship with oncology: imaging technologies and radiotherapy have been

part of the clinical setting for a long time now. However, in the computational setting, physical oncology is

oriented to the generation of integrative, mechanistic-driven models based on molecular cancer

information [154]. An advantage of this approach is that models are able to refine experimental work.

Furthermore, several problems in current oncological research can be mapped to equivalent physical

problems for which solutions have already been proposed: Problems such as cancer initiation/growth,

temporality, the role of microenvironment, metastases, etc. The role of quantitative physical oncology will

become increasingly important, as new technologies allow the measurement of quantitative parameters in

the preclinical and clinical setting [155].

Tumor growth models

The development of tumor growth models, based on quantifiable clinical observations is an important area

of research. The history of tumor growth modelling goes back to the early 20th century, with kinetic models

of cell proliferation [156]. Tumor growth can be thought of as a deregulated interaction between

environmental constraints and the cell program, and so models have moved forward by considering the

interactions between tumor, microenvironment and vascularization [157, 158].

Tumor growth modelling is generally divided in two classes: discrete and continuum modelling. Discrete

modelling uses experimentally derived rules to define the stepwise or discrete interactions between

individual cells and provide biological insights. In continuum modelling tumors are seen continuous tissue,

described in terms of morphology and nutrient distribution, using partial differential equations [159–161].

Hybrid models are gaining traction for the modelling of tumor growth. This systems couple continuous (ie.

reaction diffusion) and discrete (ie. Agent-based) formalisms for the description of tumor evolution [162].

The number of cells that these models can handle is inversely proportional to the detail of individual

cellular geometry [163]. The hybrid approach lends itself to multi-scale modelling: integrating data from

the subcellular, cellular, and tissue level in order to increase the relevance of the prediction.

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Tumor growth models may be exponential linear, Gompertzian, Bertalanffyan, etc. Independent of their

nature, tumor growth models shall be validated [164]; For instance, mathematical modelling [165]

identified unstable tumor morphologies associated to nutrient spatial variations in an in vitro spheroid

model. However, just as not all cancers conform to the same biological model [166], each mathematical

model may be valid only for a certain pathological manifestation [167].

Growth models are constantly developed [168–171] in which tumor morphologies are driven by nutrient

spatial variations. Particularly noticeable is recent work [172], which describes near criticality in a model of

early tumor growth. The authors of said work argue that this result supports proposed roles of cancer stem

cells in tumor growth.

Modeling drug efficacy in tumors

Models able to predict pharmacological response have a self-evident clinical importance. These models

need to take into account the cellular heterogeneity of tumors, interactions with the microenvironment,

interactions with immune system, reactions to therapy, and the rise of therapeutic resistance [173].

Pharmacokinetic/Pharmacodynamic (PK/PD) models have been used for the study of cancer drugs. Drug

concentration over time is coupled with response information in order to produce said models. The

simplest approach is a direct model, simply a pharmacokinetic model coupled to dose response equations

(for instance, agent-based models [174]). For drugs that do not exhibit an immediate effect, Indirect

models are generally more appropriate. [175]

Anticancer drugs generally act upon processes in a delayed time frame, making the use of special indirect

models necessary. Cytokinetic models consider the progression of cell cycle. This type of model is

particularly useful when studying agents that affect cells in a particular stage of the cycle: DNA damaging

agents, tubulin polymerisation inhibitors, apoptosis inducing drugs, etc. [175]. Drugs that act upon

signalling pathways, in the other hand, may benefit from a pathway-based model approach. Signalling

pathways are usually part of a large biological network with several interactions and complex mechanisms

of regulation, some of which may have impact on drug efficacy [176, 177]. Oncogenic singling networks

are complex and present features such as modularity, redundancy, adaptation, heterogeneity, which make

them robust (that is, resistant) to targeted perturbation [178]. Detailed pathway models [179] are useful

tools to model anticancer drug effects.

In the clinical setting PK/PD models can be used for therapeutic drug monitoring and dosing optimization

[180] in order to maximize therapeutic efficacy and reduce toxicity. A multi-scale computational model

[181] incorporates local drug, oxygen and nutrient concentrations within the three-dimensional tumor

volume to quantify the diffusion barrier effect on doxorubicin efficacy. Another use of coupled PK/PD

models is found in [182], where the effects of drugs on tumor progression in an experimental model of

tumor bearing mice are modelled using Gompertztype growth law and a pharmacokinetic

pharmacodynamic approach, and control algorithms are used to propose optimal therapeutic patterns. In

[183] a multi-scale model, with a set of stochastic differential equations to describe pharmacokinetics,

cellular dynamics, and progression free survival at the patient level, was able to identify different synergy

patterns in combination therapies. Intelligent dosing regime design remains an important factor for

anticancer therapeutic efficacy [173], and the successful implementation of rational, computer aided

systems may soon have a clinical impact.

Tumor metabolism models

Metabolism has been at the centre of many cancer studies recently [50, 184, 185]. It is natural to look for

ways to model metabolic reactions in cancer. Unlike other omics, the technology to generate large

metabolomic data is still emerging [186], but quickly evolving [187]. Metabolic cantered studies have

found, however, important results with potential clinical application [188, 189].

Biochemical processes can be modelled as serial reactions, with concentrations of reactants and products

related by reaction rates and equilibrium constants. These reactions, at the genome scale, can be

abstracted and represented as a metabolic reconstruction [190], using top-down (data-driven), bottom-up

(manually curated) or mixed approaches [191]. A stoichometric matrix is a mathematical object that

relates each chemical species with a particular reaction.

Two schools of metabolic modelling exist: kinetic modelling and constraint based modelling. Kinetic

modelling aims to characterize fully the mechanics of each enzymatic reaction. The major limitation of

these approaches is in the parameterization of mechanistic models, which is costly in resources and time

[192].

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Constraint based modelling (CBM) is largely used in the context of metabolic analysis [193]. In a CBM,

feasible phenotypic states compose a solution space. These are limited based on assumptions on the

metabolic reconstruction, such as mass balance, energy balance, thermodynamics and flux limitations,

etc. This approach requires less experimental data, but such methods are unable to give insight into

cellular substrate concentrations [194]. Flux based models are constructed under a steady state

assumption, with constrains imposed by the metabolic network’s stoichiometry, thermodynamics, and

measured rates [195]. [196] Reconstruction of a generic metabolic network model of cancer cells. Model

is reconstructed by collecting the available data on tumor suppressor genes. Notably, we show that the

activation of oncogene related reactions can be explained by the inactivation of tumor suppressor genes.

Metabolic modelling is being used to identify molecules and reactions of importance to cancer cells. In

recent work [196], a constraint-based model was able to identify a relation between oncogene related

reactions and the inactivation of tumor suppressor genes. In [197] the role of five metabolic genes

susceptible to pharmacological modulation in clear cell renal carcinoma was identified. Another use of

constraint-based models is found in [198], to study a mutually beneficial coupling between aberrant and

non-aberrant cells through the recycling of metabolic products. In [199] use results of flux-based analysis

to support an origin in metabolic adaptation to the Warburg effect.

Fig: 3. Biological levels in computational oncology. Life (and dis-ease) is comprised of different description layers.

Therefore, computational oncology has applications in a range that comprises genetic information at the sequence level, gene expression and corresponding transcriptional networks, protein interactions and functional pathways, and the interactions between cells and tissues. In addition, Computational approaches to drug therapeutics involve the modeling of drug absorption, distribution, metabolism and excretion, as well as the molecular interactions of drugs with their therapeutic targets. …………………………………………………………………………………………………………………………………………………

Integrative frameworks

Integration in computational oncology must include both, conceptual and theoretical formalism to consider

all the available information at a glance in order to catch and unveil hidden interactions and to discover

emergent phenomena (say, for instance, hormone mediated drug resistance mechanisms), but also

integration of data in computational platforms by developing algorithms to deal with multilevel and multi-

scale data.

We have already talked about the former integration scheme. The goal in the latter (let us call it

bioinformatics) issue is to be able to connect all information of a patient: her/his electronic medical

records, biochemical tests, imaging materials, as well as the available genomic, proteomic and

metabolomic data into a single, easy to use computational platform. In this regard, there has been a lot of

development in programming languages and environments such as: biopython, bioPerl, Biolinux,

bioconductoR, and so on. Some of these approaches have been largely used in the biomedical resarch

setting but important efforts are being carried out to make their way to the translational and clinical

applications.

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Even more pertinent for the advancement of computational oncology than the above mentioned software

tools is the development of suites or even initiatives that may nourish on these algorithms to built

comprehensive strategies for the treatment of cancer [200] comprising the molecular, clinical, and even

social/epidemiological dimensions of the disease, firmly founded on the use of all the computational

resources already mentioned [201].

Ironically, the rise of personalized, precision medicine has to be built upon a large scale collective effort.

An effort that should comprise the collaboration of basic scientists, translational experts and clinicians

working side by side with quantitative researchers to create such all inclusive platforms.

CONCLUDING REMARKS

In the preceding review article we outlined some of the major challenges that biomedical and clinical

research in oncology face at the light of the nascent paradigm of personalized medicine. We also

mentioned how a number of quantitative disciplines are drawn together to face the computational side of

the issue (which is no minor part at all). There are a number of short term goals that have been

accomplished in the past few years.

However, the major obstacles consist not only in solving the individual parts of the cancer puzzle (a task

that is in fact daunting for most of these parts) but also how to put all the pieces of information together in

a coherent form (i.e. how to solve the puzzle) that at the same time is comprehensive enough to deal with

the gigantic heterogeneity that cancers have at the individual level (a goal of precision medicine) but also

is able to bring answers in times reasonable enough to be useful in the clinical setting [202] and is

compliant with ethic considerations regarding confidentiality (most of the proposed approaches to date

have a component of cloud-based solutions), and the differences in criteria for research and clinical use of

patient information. Even at the light of such an enormous task, what we have accomplished in the past

give us some reasons to be optimistic.

AUTHOR CONTRIBUTION GDJ and EHL write down the manuscript; GDJ designed the figures; EHL outlined the contents for the review article; both authors (GDJ and EHL) read and approved the submitted version of the manuscript.

CONFLICT OF INTEREST The authors declare no competing interests. ACKNOWLEDGEMENT The authors are grateful to the funding institutions for support provided. FINANCIAL DISCLOSURE The present research program has been funded by the National Council on Science and Technology (CONACYT) under grant number 179431/2012, as well as from federal funding provided by the National Institute of Genomic Medicine (both Mexican-based Institutions). The founders had no role in the design of the research.

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