ON-DEMAND ONLY: Beyond Genomics: Protein Drug Target Activation Mapping to Change the Paradigm in Precision Medicine Based Cancer Therapy

Genomic analysis of cancer has revealed the tremendous heterogeneity of cancer at the individual level, and that ultimately 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 current and new molecular guided therapeutics, it is critical that we begin to define and treat human cancer at a functional protein pathway activation level. Indeed, systems biology type approaches that use proteomic, transcriptomic, and DNA mutational analysis concomitantly may hold the key for effective therapy. Post-translational modification such as phosphorylation drive and underpin nearly all cell signaling processes that are aberrantly activated in cancer and therapeutic resistance, and are epigenetic events that are not predictable using genomic approaches alone. 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 drug targets, governing cellular survival, proliferation, invasion and cell death. The reverse phase protein microarray (RPPA) technology, when coupled to laser capture microdissection (LCM) is now being routinely utilized to generate a functional map of known cell signaling networks or pathways for an individual patient obtained directly from a biopsy specimen.  From a single biopsy specimen, the activation or “in use” state of over 200 protein drug targets can be quantitatively measured at once, providing unprecedented opportunity to measure the direct targets of nearly every FDA cleared and experimental targeted inhibitor at once from just a small piece of a single biopsy sample. The LCM-RPPA technology platform is now available as an automated commercial CLIA LDT assay that has now been launched as the Theralink Assay™, which measures a targeted panel of 32 proteins and phosphoproteins and is delivered in a 14 day turn-around-time from FFPE material.  This patient-specific pathway activation map provide key information that identifies actionable targets for individualized or combinatorial therapy through the quantification of phosphorylation states of proteins. In addition to the commercial CLIA LDT assay, protein pathway activation mapping via the LCM-RPPA platform is being implemented in a number of ongoing precision oncology trials and as a key component of therapy decision making and CDx development.