Proteotyping For Drug Development: Proteomics Impacting Clinical Practice

The road to medical translation starts with understanding of an individual's history and disease status via the quantification of proteins and their disease‐induced modified forms. Each individual's proteome reflects both their cellular memory and current health status and should allow prediction of their response to environment and therapeutic treatment. Thus, precision medicine maybe feasible but it will require the ability of specific drug targeting at the level of an individual. One example is the targeting of drugs to activate the protein kinase G (PKG) pathway, which in animal studies have been shown to blunt the development of heart failure. Drugs that inhibit the breakdown of cGMP (thus, activating PKG) have had less than expected therapeutic efficacy in numerous clinical trials. We have recently shown that there are multiple unanticipated levels of regulation of the PKG pathway that influence which subproteome is affected by PKG that ultimately leads to varied functional consequences. This includes an individuals’ redox status and heart failure type (e.g heart failure with preserved ejection fraction) that should affect the effectiveness of the current PKG‐targeted drugs. Similarly, resynchronization therapy, one of the few clinically used treatments for heart failure where dual pacemakers are implanted to ensure coordinated cardiac pumping, activates GSK 3 beta altering the contractile subproteome. This kinase is also influenced by the redox status and the oxidation of GSK 3 beta changes its downstream targets and potentially the functional outcome. Methods to assess individual's status prior to treatment selection will increase efficacy and patient selection as well alteration to their basal/pretreatment status could increase an individual's response to therapy. Support or Funding Information P01 HL77189‐01 , R01HL119012 , NHLBI‐HV‐10‐05 (2)