Abstract:
:Breast cancer (BC) is the most common cancer in women, and the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct morphologies and clinical implications. Quantitative systems pharmacology (QSP) is an emerging discipline bridging systems biology with pharmacokinetics (PK) and pharmacodynamics (PD) leveraging the systematic understanding of drugs' efficacy and toxicity. Despite numerous challenges in applying computational methodologies for QSP and mechanism-based PK/PD models to biological, physiological, and pharmacological data, bridging these disciplines has the potential to enhance our understanding of complex disease systems such as BC. In QSP/PK/PD models, various sources of data are combined including large, multi-scale experimental data such as -omics (i.e. genomics, transcriptomics, proteomics, and metabolomics), biomarkers (circulating and bound), PK, and PD endpoints. This offers a means for a translational application from pre-clinical mathematical models to patients, bridging the bench to bedside paradigm. Not only can these models be applied to inform and advance BC drug development, but they also could aid in optimizing combination therapies and rational dosing regimens for BC patients. Here, we review the current literature pertaining to the application of QSP and pharmacometrics-based pharmacotherapy in BC including bottom-up and top-down modeling approaches. Bottom-up modeling approaches employ mechanistic signal transduction pathways to predict the behavior of a biological system. The ones that are addressed in this review include signal transduction and homeostatic feedback modeling approaches. Alternatively, top-down modeling techniques are bioinformatics reconstruction techniques that infer static connections between molecules that make up a biological network and include (1) Bayesian networks, (2) co-expression networks, and (3) module-based approaches. This review also addresses novel techniques which utilize the principles of systems biology, synthetic lethality and tumor priming, both of which are discussed in relationship to novel drug targets and existing BC therapies. By utilizing QSP approaches, clinicians may develop a platform for improved dose individualization for subpopulation of BC patients, strengthen rationale in treatment designs, and explore mechanism elucidation for improving future treatments in BC medicine.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Fleisher B,Brown AN,Ait-Oudhia Sdoi
10.1016/j.phrs.2017.07.015subject
Has Abstractpub_date
2017-10-01 00:00:00pages
20-33eissn
1043-6618issn
1096-1186pii
S1043-6618(17)30312-2journal_volume
124pub_type
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