Organizer : Eugene C. Yi (Seoul National University, Korea)
We intend to discuss the role proteomics in precision medicine, which is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. As the field of precision medicine is gained increasing public attention with Obama initiative, efforts are underway to help make proteomics as a valuable first-line tool for shaping the growing field of precision medicine. In this session, we discuss the technologies used in proteomics and hear from leading researchers about how the use of the integrated discipline(genomics/proteomics) is guiding precision medicine today and the role of proteomics in the future.
Mining drug-resistant target from large-scale determination of absolute phosphorylation stoichiometries in cancer cell
Abstract
Direct measurement of the phosphorylation stoichiometry can unambiguously reveal whether the signal-induced alteration is regulated by upstream kinase/phosphatase activity or by transcriptional regulation to modify protein abundance. Although MS-based approach has been used to quantify expression of phosphopeptides for several thousand sites, the absolute phosphorylation stoichiometry has not been measured yet. To overcome the current bottleneck in accessing the stoichiometry of human phosphoproteome in single cell status, we have developed a motif-targeting quantitative proteomic approach to measure the absolute phosphorylation stoichiometry on a large scale.
The performance of this approach was evaluated to measure the absolute stoichiometry as well as to compare the phosphoproteomic alterations between the targeted-therapy sensitive and resistance lung cancer cell lines. The proof-of-concept experiments using CK2-, MAPK- and EGFR-targeted assays demonstrated the advantage of kinase-targeted complexity reduction for deeper phosphoproteome. With 50μ glysate, phosphorylation stoichiometry of >1000 phosphorylation sites including 366 low abundant tyrosine phosphorylation sites were successfully measured with high reproducibility (standarddeviation: ±6%). To our knowledge, this approach reveals the first large-scale measurement on the basal level of phosphorylation stoichiometry in a single human phosphoproteome. Such quantitative information illuminated that the post-translational phosphorylation changes associated with drug resistance in cancer are significantly more dramatic than those at protein as well as at mRNA levels. Through network analysis, the measurement identified a substrate of CK2 in the kinase-substrate network associated with acquired drug-resistance. We expect this motif-targeting quantitative approach may be useful to study phosphorylation-mediated events from broad ranges of fundamental research to discovery-driven cancer research.
Patient-derived xenograft model for breast cancer research
Abstract
Patient-derived xenograft model (PDX model) is a promising tool to study the characteristics of various solid tumors. There are general expectations that the PDX model can be used as a platform to study the individual patient’s sensitivity to targeted agents as well as its ability to guide our understanding in tumor biology including the tumor’s clonal evolution.
We have focused on the development of PDX model by using primary breast tumor tissue obtained during the surgery in Seoul National University Hospital. Since 2011, we have performed more than 300 xenotransplantation of primary breast tumors into the NSG mouse. Our experience of PDX model in breast cancer as well as its potential utility in developing effective biomarker in breast cancer will be discussed in my presentation. Briefly, we have focused on identifying a novel prognostic gene signature in triple negative breast cancer patients using the PDX model.
In this presentation, I will introduce our previous experience with the use of the PDX models in biomarker discovery in breast cancer. Additionally, I will briefly discuss the current understanding of the genomic evolution in PDX tumors after engraftment. Finally, I will share our prelimimary data on the proteogenomic data acquisition in breast cancer PDX models.
Novel Proteoforms: Databases, Search Strategy, and Validation
Abstract
Proteogenomics research usually includes searching proteomic data against genomic databases, hoping to find evidence of novel proteoforms that may result from novel genomic, transcriptomic, or translational events. We are interested in a variety of novel events such as non-synonymous SNPs, insertions and delections, alternative splicing, frame shifts and translated UTRs, because they are believed to be on the trail of the “Holy Grail” in cancer therapy. Naturally, there are many pitfalls and dangers on the Holy Grail trail. Thus, we cannot be too careful in choosing databases and search strategies and validation methods. First, we will see ways to construct genomic databases and their implications. Second, search strategies and FDR estimation methods need to be carefully chosen to discover novel peptides in a sensitive and robust manner. Finally, software tools can be very helpful for aligning novel peptides to the reference gene model, making it possible to understand the underlying novel genomics/transcriptomic/translational events.
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