HCG Isoform Markers of Trophoblastic Malignancies

滋养细胞恶性肿瘤的 HCG 亚型标志物

• 批准号: 6784718
• 负责人: Steven Birken
• 金额: $ 20.44万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6784718
• 关键词: biomarker; carbohydrates; choriocarcinoma; chorionic gonadotropin; clinical research; diagnosis design /evaluation; embryo neoplasm; glycoprotein structure; glycosylation; human tissue; immunologic assay /test; neoplasm /cancer immunodiagnosis; pregnancy disorder; protein isoforms; trophoblast; women' s health

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.

描述（由申请人提供）：HCG 是妊娠期和非妊娠期滋养细胞疾病的主要肿瘤标志物。部分或完全性葡萄胎妊娠后，一些患者会出现恶性妊娠滋养细胞疾病。患者可能会出现不明原因的循环 hCG 升高，但没有临床疾病的证据，并且仅因为其 hCG 标记物而接受治疗。根据 hCG 标记检测，其他接受治疗的患者会出现治疗耐药或复发。我们建议评估我们实验室最近开发的几种新的 hCG 亚型免疫测定法作为改进的 hCG 相关肿瘤标志物的效用。新的标记物可能有助于识别需要化疗的女性亚群以及在葡萄胎癌前妊娠后将出现自发缓解的女性亚群。新标记物还可以改善妊娠和非妊娠滋养细胞疾病患者（包括睾丸癌）的治疗护理。这些标记物基于四种差异化免疫测定系统： 1. hCG 的碳水化合物相关变体。 2.“切口”形式的 hCG。 3.“切口”和高糖基化的同工型。 4. hCG 和 hLH β 核心片段。大多数这些 hCG 同工型已被证明在恶性肿瘤中发生了结构改变，但之前不存在量化这些同工型的测定测量系统。健康个体（来自垂体）产生的 hCG 同工型必须与恶性组织产生的 hCG 同工型明确区分。碳水化合物变异体 hCG 亚型的检测基于抗体 B152（针对绒毛膜癌分泌的 hCG 亚型而开发），该抗体可检测妊娠早期以及各种恶性肿瘤中产生的差异 O-糖基化形式的 hCG。据报道，分泌 HCG 的癌症会产生“带切口”的 hCG 同工型，其 β 亚基内有肽键裂解。这些将通过测定系统 (B151) 结合快速色谱程序进行测量。绒毛膜癌和其他滋养层细胞癌产生同工型，它们都是“切口”和高糖基化的。这些可通过 B151 捕获 B152 检测测定进行检测。还开发了专门测量尿 hCG 和尿 hLH 代谢物的系统，以便可以将绝经后妇女的 hCG 相关代谢物与正常 hLH 代谢物区分开来。将进行结构分析以将异构体结构与测定测量相关联。