IDENTIFICATION OF PANCREATIC CANCER-SPECIFIC ANTIGENS USING A NOVEL QUANTITATIVE SEROPROTEOMICS APPROACH
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Date
2014-03-19
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Johns Hopkins University
Abstract
Pancreatic ductal adenocarcinoma (PDA) is among the most deadly cancers with less than 5% of the patients living beyond 5 years after diagnosis. Lack of early diagnostic biomarkers and resistance to current therapies help explain these disappointing outcomes. Thus, more effective and better-targeted therapies are quickly needed. Monoclonal antibodies offer an attractive alternative targeted therapy option for PDA. However, currently available monoclonal antibody therapies for PDA are still in its infancy with a low success rate of being approved and are facing several challenges. Discovery of novel PDA-specific antigen targets is needed. Predictive and response markers also need to be determined for PDA patient subgroups so that the most appropriate effective therapy can be delivered. Our group has developed a PDA vaccine that has recently completed phase II clinical trials. Here, we employed a novel quantitative seroproteomics approach, SASI, to identify proteins that elicit an increased antibody response post-vaccination. The SASI approach utilizes immunoprecipitation by serum antibodies, which is coupled to the quantitative SILAC. Using mass spectrometry analysis, regulatory subunit 8 of the 26S proteasome (PSMC5), regulatory subunit 12A of protein phosphatase 1 (MYPT1 or PPP1R12A) and transferrin receptor (TFRC) were shown to be PDA-associated antigens that were recognized by post-vaccination antibodies in the sera of patients that received the vaccine and have demonstrated a favorable disease free survival (DFS). We further analyzed PSMC5, MYPT1 and TFRC for tissue expression in normal and PDA specimens and found these proteins to increase in expression with tumor development. Most significantly, the antibody responses detected against these proteins in patients with an improved DFS suggests an anti-tumor potential of targeting these proteins. Overall, our data demonstrates that the novel SASI approach can identify candidate proteins as possible new biomarkers for screening and as new targets for therapeutic intervention. Traditional and new serologic approaches, recombinant antibody producing technologies and advances in antibody engineering techniques will help identify additional predictive biomarkers and aid in the development of new therapeutic antibodies. A combinatorial approach simultaneously targeting antigens on the PDA cell, stroma and immunosuppressive cells should be employed to successfully treat PDA.
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Pancreatic cancer