Colorectal cancer strikes over 150,000 men and women in the U.S. each year. Most cases are not detected until advanced stages and hence are associated with poor survival rates. By contrast, when tumors are detected at early stages, standard treatments can result in five-year survival rates of 90 percent. Currently, only 37 percent of cases are detected at an early stage, therefore the survival rate could be significantly increased by introduction of a sensitive and specific screening test to detect early-stage malignancy. The immune system responds to early-stage tumors by producing serum antibodies that recognize tumor-associated proteins, or """"""""tumor antigens."""""""" These antibodies are found in circulation and can potentially be used as indicator proteins in a screening test. The applicant hypothesizes that most, if not all, early-stage cancer patients mount an antibody response to their tumor, with each patient recognizing one or more members of a large set of potential antigens.
In Aim l, the serum antibody response to five known antigens (HER2/neu, p53, CO-8, CO-9 and CO-38) will be measured in early-stage colorectal cancer patients and normal controls. It is expected that these five antigens will be recognized by serum antibodies from some early-stage cancer patients but not others.
Aim 2 will focus on the identification of new tumor antigens that elicit serum antibody responses in the latter group of patients (i.e., those who do not respond to known tumor antigens). New antigens will be discovered by the SEREX immunoscreening technique, in which an early-stage colorectal tumor cDNA expression library will be screened for immunoreactivity to patient antibodies. Immunoscreening will be performed in a recursive manner to identify a panel of tumor antigens that, when combined with the five known antigens from Aim 1, allows detection of the maximal number of patients, while correctly excluding normal controls, In addition to addressing fundamental issues of antigen diversity and immune responsiveness in human cancer patients, this study may lead to a prototype screening test for colorectal cancer that, in the future, would be subjected to formal validation in expanded, prospective study populations.
