Development and Clinical Implementation of Reverse Phase Protein Microarrays for Protein Network Activation Mapping: Personalized Cancer Therapy

Abstract

Recently, whole genome mutational scanning analysis of a number of solid tumors has revealed that cancer is a protein pathway disease at the functional level. However, since genomic and transcript profiling likely cannot alone sufficiently predict protein pathway activation in each patient’s tumor, and it is these signaling pathways that represent the targets for new molecular guided therapeutics. Thus, it is critical that we begin to define human cancer at a functional pathway activation level. Post-translational modifications such as phosphorylation drive and underpin nearly all cell signaling processes that are aberrantly activated in cancer and are epigenetic events, and not necessarily directly predictable using genomic approaches. In fact, cancer, as a model for human disease, is a manifestation of deranged cellular protein molecular networks and cell signaling pathways that are underpinned by genetic changes. These pathways contain a large and growing collection of drug targets governing cellular survival, proliferation, invasion and cell death. We have developed a new type of technology, termed reverse phase protein microarray, to generate a functional map of known cell signaling networks or pathways for an individual patient using tissue obtained directly from a biopsy specimen. This patient-specific “circuit diagram” provides key information for individualized therapy. The identification of activated protein drug target networks can be used as patient selection and stratification: the realization of pathway biomarkers as perhaps the ultimate companion diagnostic assay for systems medicine.