Diagnostic Biomarkers and Therapeutic Targets for Pancreatic Cancer

Abstract

We identified >40 proteins that elicited at least a 2-fold increase in antibody response post-pancreatic-cancer vaccination, from each of three patients' sera. The antibody responses detected against these proteins in patients with >3 years disease-free survival indicates the anti-tumor potential of targeting these proteins. We found that tissue expression of proteins PSMC5, TFRC and PPP1R12A increases during tumor development from normal to pre-malignant to pancreatic tumor. In addition, these proteins were shown to be pancreatic cancer-associated antigens that are recognized by post-vaccination antibodies in the sera of patients that received the vaccine and have demonstrated a favorable disease free survival.

1 . A method for detecting pancreatic cancer in a body sample from a human, comprising:
 contacting the body sample with at least one antibody that specifically binds to a protein selected from the group consisting of: Transferrin receptor (TFRC), regulatory subunit 12A of protein phosphatase 1 (PPP1R12A), and regulatory subunit 8 of the 26S proteasome (PSMC5);   detecting amount of antigen bound to the antibody or cellular localization of the antigen, wherein an increased amount of antigen bound to the antibody relative to an amount bound to a control sample or an altered cellular localization indicates the presence of a pancreatic cancer.   
     
     
         2 . The method of  claim 1  wherein the body sample is a tissue sample. 
     
     
         3 . The method of  claim 1  wherein the body sample is a blood or urine sample. 
     
     
         4 . The method of  claim 1  wherein the step of detecting is performed using immunohistochemistry. 
     
     
         5 . The method of  claim 1  wherein the step of detecting is performed using an ELISA. 
     
     
         6 . The method of  claim 1  wherein at least two of said antibodies are contacted and detected. 
     
     
         7 . The method of  claim 1  wherein at least three of said antibodies are contacted and detected. 
     
     
         8 . The method of  claim 1  wherein the steps of contacting and detecting are further performed using at least one antibody that specifically binds to an antigen selected from the group consisting of: mesothelin, annexin A2, and galectin 3. 
     
     
         9 . A method for monitoring progression of pancreatic cancer in a body sample from a human, comprising:
 contacting the body sample with at least one antibody that specifically binds to a protein selected from the group consisting of: Transferrin receptor (TFRC), regulatory subunit 12A of protein phosphatase 1 (PPP1R12A), and regulatory subunit 8 of the 26S proteasome (PSMC5);   detecting amount of antigen bound to the antibody, wherein an increased amount of antigen bound to the antibody relative to an amount bound to a sample taken at a prior time indicates progression of the pancreatic cancer and a decreased amount of antigen bound to the antibody relative to amount bound to a sample taken at a prior time indicates responsiveness to an anti-cancer treatment.   
     
     
         10 . The method of  claim 9  wherein the body sample is a tissue sample. 
     
     
         11 . The method of  claim 9  wherein the body sample is a blood or urine sample. 
     
     
         12 . The method of  claim 9  wherein the step of detecting is performed using immunohistochemistry. 
     
     
         13 . The method of  claim 9  wherein the step of detecting is performed using an ELISA. 
     
     
         14 . The method of  claim 9  wherein at least two of said antibodies are contacted and detected. 
     
     
         15 . The method of  claim 9  wherein at least three of said antibodies are contacted and detected. 
     
     
         16 . The method of  claim 9  wherein the steps of contacting and detecting are further performed using at least one antibody that specifically binds to an antigen selected from the group consisting of: mesothelin, annexin A2, and galectin 3. 
     
     
         17 . A method to predict response to a pancreatic cancer vaccine in a human, comprising:
 contacting a body sample of the human with at least one antibody that specifically binds to a protein selected from the group consisting of: Transferrin receptor (TFRC), regulatory subunit 12A of protein phosphatase 1 (PPP1R12A), and regulatory subunit 8 of the 26S proteasome (PSMC5);   detecting amount of antigen bound to the antibody, wherein a decreased amount of antigen bound to the antibody relative to an amount bound to a control sample prior to vaccination predicts long term disease-free survival.   
     
     
         18 . The method of  claim 17  wherein the body sample is a tissue sample. 
     
     
         19 . The method of  claim 17  wherein the body sample is a blood or urine sample. 
     
     
         20 . The method of  claim 17  wherein the step of detecting is performed using immunohistochemistry. 
     
     
         21 . The method of  claim 17  wherein the step of detecting is performed using an ELISA. 
     
     
         22 . The method of  claim 17  wherein at least two of said antibodies are contacted and detected. 
     
     
         23 . The method of  claim 17  wherein at least three of said antibodies are contacted and detected. 
     
     
         24 . The method of  claim 17  wherein the steps of contacting and detecting are further performed using at least one antibody that specifically binds to an antigen selected from the group consisting of: mesothelin, annexin A2, and galectin 3. 
     
     
         25 . A kit for detecting or monitoring pancreatic cancer disease or therapy, comprising:
 at least one antibody that specifically binds to an antigen selected from the group consisting of: Transferrin receptor (TFRC), regulatory subunit 12A of protein phosphatase 1 (PPP1R12A), and regulatory subunit 8 of the 26S proteasome (PSMC5);   a detection means for detecting binding complexes of the antibody and antigens in a test sample.   
     
     
         26 . The kit of  claim 25  further comprising a solid support for binding antibodies, antigens, or antibody-antigen complexes. 
     
     
         27 . The kit of  claim 25  wherein the detection means comprises an enzyme that can produce a colored reaction product. 
     
     
         28 . The kit of  claim 25  wherein the detection means comprises a second antibody that binds to said at least one antibody. 
     
     
         29 . A method to predict response to a pancreatic cancer vaccine in a human, comprising:
 contacting a sample of the human comprising antibodies with at least one protein selected from the group consisting of: Transferrin receptor (TFRC), regulatory subunit 12A of protein phosphatase 1 (PPP1R12A), and regulatory subunit 8 of the 26S proteasome (PSMC5);   detecting amount of antibody bound to the at least one protein, wherein an increased amount of antibody bound to the at least one protein relative to an amount bound to a control sample prior to vaccination predicts long term disease-free survival.   
     
     
         30 . The method of  claim 29  wherein the body sample is a tissue sample. 
     
     
         31 . The method of  claim 29  wherein the body sample is a blood or urine sample. 
     
     
         32 . The method of  claim 29  wherein the step of detecting is performed using immunohistochemistry. 
     
     
         33 . The method of  claim 29  wherein the step of detecting is performed using an ELISA. 
     
     
         34 . The method of  claim 29  wherein at least two of said antibodies are contacted and detected. 
     
     
         35 . The method of  claim 29  wherein at least three of said antibodies are contacted and detected. 
     
     
         36 . The method of  claim 29  wherein the steps of contacting and detecting are further performed using at least one antibody that specifically binds to an antigen selected from the group consisting of: mesothelin, annexin A2, and galectin 3. 
     
     
         37 .- 90 . (canceled)