More than 70% of women diagnosed with ovarian carcinomas are likely to die from progressive disease; although combination chemotherapy often causes a complete clinical remission, the remissions are commonly not sustained. The applicant's goal is to decrease mortality by finding ways to detect ovarian carcinomas earlier and by developing a therapeutic vaccine causing the immunological destruction of those cancer cells remaining after chemotherapy. A prerequisite for these goals is existence of antigens commonly expressed by ovarian carcinomas and rarely in normal tissues. These antigens can serve as diagnostic markers and therapeutic targets. This project focuses on molecules that belong to the mesothelin-megakaryocyte potentiating factor (MPF) family and that are overexpressed in more than 90% of ovarian carcinoma. She has made several mouse Mabs that bind to the C-terminal membrane associated domain but not to the N-terminal 30 kd or 33 kd parts normally cleaved during cellular processing. She recently discovered a new member of the mesothelin/MPF family, which has an 82bp insertion, lacks a stop codon, and is expected to have a soluble rather than membrane-bound C-terminal domain. To the extent tested, the 82 bp insertion has only been detected in ovarian carcinomas and subgroups of some other tumors. Soluble mesothelin-related (MR) molecules can be detected in sera from patients with ovarian carcinoma as a tumor marker, and she hypothesizes that the newly discovered molecule with the 82 bp insert is this marker. She now proposes, first, to further investigate the characteristics of that molecule with respect to its tumor specificity, to make Mabs to the 98AA new C-terminus encoded by the 82 bp insertion and the frameshift of 212 bp it causes, and to study whether they offer advantages for detecting antigen in serum. Second, she shall investigate whether a serum assay for MR molecules facilitates the early diagnosis and """"""""monitoring"""""""" of patients with ovarian carcinoma, when used alone or in combination with an assay for CA125. Third, she shall study whether patients with ovarian carcinoma make antibodies to MR molecules, and, if so, whether detection of such antibodies facilitates early diagnosis. Finally, she shall investigate whether an immune response can be generated, in vitro, against (non-soluble) mesothelin and/or against the soluble MR molecule. This will be approached using gene based tumor vaccine(s), taking into account what has been learned about the role of costimulation, via CD80/CD86 and signaling, via 4-lBB. As part of this study, she shall investigate whether the soluble MR molecule (SMR) can act as an inhibitor of the immune response and, if so, whether the inhibition can be overcome.
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