Integration of Protein Network Activation Mapping Technology for Personalized Therapy: Implications for Pancreatic Cancer

Introduction

The underpinning and ultimate promise of personalized therapy is that the molecular fingerprint of a patient’s tumor becomes the rationale for targeted and patient-tailored therapy. Until recently, this fingerprint has been a genomics-centered analysis using exome panels, whole genome sequencing, and/or RNA sequencing comprising the details that most scientists and treating oncologists consider when considering a “precision medicine”–based approach. Stratification and selection of patients for certain targeted therapies based on genomics analysis has certainly been successful in a number of instances such as with non-small cell lung cancer (NSCLC), where EGFR mutations and ROS/ALK translocations can be highly predictive for therapeutic response, or HER2 amplification in breast cancer , BRAFV600E mutations in melanoma , etc., but these approaches have imperfect sensitivity and specificity and often show little to no predictive value .

However, while these examples show the potential for genomic-based therapy prediction, not every NSCLC patient that harbors an EGFR mutation responds to EGFR-directed therapy, not every HER2+ breast cancer responds to Herceptin™, etc., thus genomic derangement analysis alone is unable to completely explain all targeted therapeutic response even in an enriched population. Cancer is certainly causally determined by specific genomic derangements, but in fact cancer is a proteomic disease. It is the proteins that are the “software” of the cell and do nearly all the work of the cell. More practically, the mechanism of action of most cancer therapies works at the protein level and protein enzymatic level (e.g., kinase inhibitors). It is proteins that are the drug targets and make up the signaling circuitry and biochemical networks of the cell. When scientists refer to aberrant signaling “pathways” or targeting cellular “networks”, it is the proteins, not genes that make up these pathways and networks.

Molecularly targeted agents for cancer treatment are now being cleared by the FDA on a regular basis, and thus the era of personalized therapy for cancer treatment has begun in earnest. In the near future, the oncologist will have a large number of FDA-approved agents to select from for any given patient, along with a compendium of molecular profiling–based companion diagnostic tests (CDx) that would be used for drug selection. However, based on these molecular profiling technologies, while drugs such as imatinib, sunitinib, traztuzumab, etc. have had a dramatic impact on GIST, CML renal cancer, and c-erbB2+ breast cancers, respectively, the emphasis will shift from the specific therapies themselves to the CDx biomarkers that will be used to stratify and select the right therapy for each patient. The new CDx biomarkers will serve as the gatekeepers to the drugs. Thus, CDx marker discovery is under intense current investigation because of their elevated status within the treatment selection process, and the near-future CDx will not be single markers but panels of dozens or hundreds of markers that are the gateways to dozens to hundreds of targeted therapies.

Defective Protein Signaling Networks Underpin Tumorigenesis