HCG Isoform Markers of Trophoblastic Malignancies

Columbia University Health Sciences, New York NY

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Abstract

[unreadable] DESCRIPTION (provided by applicant): HCG is the main tumor marker for both gestational and non-gestational trophoblastic disease. After a pregnancy with partial or complete hydatidiform mole, some patients develop malignant gestational trophoblastic disease. Patients may display unexplained elevation of circulating hCG with no evidence of clinical disease and are treated solely because of their hCG marker. Other patients under treatment develop resistance to therapy or relapse as detected by the hCG marker. We propose to assess the utility of several new immunoassays for hCG isoforms, recently developed in our laboratory, as improved hCG-related tumor markers. New markers may help to identify the subpopulation of women who will require chemotherapy from those who will undergo spontaneous remission after a premalignant molar pregnancy. The new markers may also improve therapeutic care for both gestational and non-gestational trophoblastic disease patients, including testicular cancers. These markers are based on four differentiating immunoassay systems to: 1.carbohydrate-related variants of hCG. 2. "nicked" forms of hCG. 3. isoforms both "nicked" and hyperglycosylated. 4. hCG and hLH beta core fragments. Most of these hCG isoforms have been shown to be structurally altered in malignancies but no assay measurement systems existed previously to quantify these isoforms. The hCG isoforms produced by healthy individuals (from pituitary) must be clearly differentiated from those isoforms produced by malignant tissues. The detection of carbohydrate-variant hCG isoforms are based on the antibody B152 (developed to choriocarcinoma-secreted hCG isoforms) which detects a differentially O-glycosylated form of hCG produced very early in pregnancy as well as in various malignancies. HCG-secreting cancers have also been reported to produce "nicked" hCG isoforms with peptide bond cleavages within the beta subunit. These will be measured by assay system (B151) in conjunction with a rapid chromatographic procedure. Choriocarcinoma and other trophoblastic cancers produce isoforms, which are both "nicked", and hyperglycosylated. These are detected by a B151 capture B152 detection assay. Systems to specifically measure urinary hCG and urinary hLH metabolites have also been developed so that hCG-related metabolites can be distinguished from normal hLH metabolites in postmenopausal women. Structural analyses will be performed to correlate isoform structures with assay measurements. [unreadable] [unreadable]