Abstract
Mapping tumor cell protein networks in vivo will be critical for realizing the promise of patient-tailored
molecular therapy. Cancer can be defined as a dysregulation or hyperactivity in the network of
intracellular and extracellular signaling cascades. These protein signaling circuits are the ultimate targets
of molecular therapy. Each patients tumor may be driven by a distinct series of molecular pathogenic
defects. Thus, for any single molecular targeted therapy, only a subset of cancer patients may respond.
Individualization of therapy, which tailors a therapeutic regimen to a tumor molecular portrait, may be the
solution to this dilemma. Until recently, the field lacked the technology for molecular profiling at the
genomic and proteomic level. Emerging proteomic technology, used concomitantly with genomic
analysis, promises to meet this need and bring to reality the clinical adoption of molecular stratification.
The activation state of kinase-driven signal networks contains important information relative to cancer
pathogenesis and therapeutic target selection. Proteomic technology offers a means to quantify the
state of kinase pathways, and provides post-translational phosphorylation data not obtainable by gene
arrays. Case studies using clinical research specimens are provided to show the feasibility of generating
the critical information needed to individualize therapy. Such technology can reveal potential new
pathway interconnections, including differences between primary and metastatic lesions. We provide a
vision for individualized combinatorial therapy based on proteomic mapping of phosphorylation end
points in clinical tissue material.
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