Abstract
BackgroundProstate cancer is one of the most prevalent cancers in males in the United States and amongst the leading causes of cancer related deaths. A particularly virulent form of this disease is castration-resistant prostate cancer (CRPC), where patients no longer respond to medical or surgical castration. CRPC is a complex, multifaceted and heterogeneous malady with limited standard treatment options.ResultsThe growth and progression of prostate cancer is a complicated process that involves multiple pathways. The signaling network comprising the integral constituents of the signature pathways involved in the development and progression of prostate cancer is modeled as a combinatorial circuit. The failures in the gene regulatory network that lead to cancer are abstracted as faults in the equivalent circuit and the Boolean circuit model is then used to design therapies tailored to counteract the effect of each molecular abnormality and to propose potentially efficacious combinatorial therapy regimens. Furthermore, stochastic computational modeling is utilized to identify potentially vulnerable components in the network that may serve as viable candidates for drug development.ConclusionThe results presented herein can aid in the design of scientifically well-grounded targeted therapies that can be employed for the treatment of prostate cancer patients.
Highlights
Prostate cancer is one of the most prevalent cancers in males in the United States and amongst the leading causes of cancer related deaths
Key cellular signal transduction pathways known to play a major role in cell survival, growth, differentiation and the development of castrationresistance in prostate cancer are the Androgen Receptor (AR), PI3K/AKT/mTOR and Mitogen-Activated Protein Kinase (MAPK) pathways
Castration-resistant prostate cancer is a hormone refractory phenotype of significant morbidity and mortality in the prostate cancer disease continuum where patients no longer respond to androgen ablation therapy
Summary
Prostate cancer is one of the most prevalent cancers in males in the United States and amongst the leading causes of cancer related deaths. A virulent form of this disease is castration-resistant prostate cancer (CRPC), where patients no longer respond to medical or surgical castration. The growth and progression of prostate cancer is stimulated by androgens [2]. It mediates transcription of target genes that modulate growth and differentiation of prostate epithelial cells. As prostate cancer relies on androgens for growth, the main line of treatment focuses on abrogating the action of androgens. Androgen deprivation therapy (ADT) in the form of surgical or medical castration is the cornerstone of treatment for prostate cancer [4]. The response to ADT is temporary and prostate cancer invariably stops responding to this treatment regimen, leading to a
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