The Pacific Northwest Proteogenomic Translational Research Center (PNPTRC) has two overarching aims: 1) to use combined measurements of protein abundance and post translational modifications, particularly phosphorylation, to build predictive models of drug response that can be effectively used to guide the choice of agents for first-line therapies, and 2) to model the processes of signaling crosstalk and redundancy to more effectively predict drug resistance and to guide second line therapies. To accomplish these goals, the PNPTRC will leverage on-going preclinical and clinical studies of individualized treatment selection strategies for acute myelogenous leukemia (AML) to improve the emerging models based on DNA and RNA data to include signal transduction pathway information derived from proteomic and phosphoproteomic measurements, and improve the predictive power of the models by integrating genomic and proteomic data. The PNPTRC represents a collaboration between innovative clinical trial design and therapeutic interventions at the OHSU Knight Cancer Center, and cutting edge mass spectrometry-based proteomics technologies at PNNL. The Preclinical Research Arm of the PNPTRC will identify differences in protein abundance and protein phosphorylation that correlate strongly with cell survival in the in vitro IC50 assay developed at OHSU. Measurements of protein abundance and phosphorylation over time of treatment will be used to build networks of pathway activation and crosstalk that can inform the likelihood of eventual resistance and identify alternative signaling pathways which can be targeted in second line therapies. The models will be further tested and refined in subsequent ex vivo experiments using primary human AML cells exposed to specific combinations of inhibitors. The Clinical Research Arm will apply high quality targeted proteomic assays on samples from AML patients enrolled in NCI-sponsored clinical trials to confirm the predictive abilities of specific differences in protein abundance and/or phosphorylation identified in the Preclinical Research Arm.
The Pacific Northwest Proteogenomic Translational Research Center will combine deep and broad measurements of protein and phosphoprotein abundance from ex vivo experiments using primary leukemia cells from patients with acute myelogenous leukemia (AML) to model the effects of targeted therapeutic agents on activation state of key signaling pathways. The predictive ability of signatures derived from the preclinical models will be tested in clinical samples from AML patients enrolled in NCI-sponsored clinical trials, using ultrasensitive targeted proteomic methods.
|Rodland, Karin D; Piehowski, Paul; Smith, Richard D (2018) Moonshot Objectives: Catalyze New Scientific Breakthroughs-Proteogenomics. Cancer J 24:121-125|