Guanylyl Cyclase C in Blood and Colorectal Cancer

血液和结直肠癌中的鸟苷酸环化酶 C

• 批准号: 6772420
• 负责人: SCOTT A WALDMAN
• 金额: $ 120.43万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772420
• 关键词: biomarker; blood tests; carcinoembryonal antigen; clinical research; colorectal neoplasms; diagnosis design /evaluation; disease /disorder onset; guanylate cyclase; human middle age (35-64); human old age (65+); human subject; messenger RNA; metastasis; neoplasm /cancer diagnosis; neoplasm /cancer relapse /recurrence; patient oriented research; polymerase chain reaction; prognosis

DESCRIPTION (provided by applicant): In the U.S., 50% of patients who undergo "curative" resection for colorectal cancer suffer recurrent disease. In part, this reflects the absence of techniques to detect occult micrometastases prior to clinically evident recurrence. Guanylyl cyclase C (GC-C) is specifically expressed by normal mucosal and colorectal cancer cells, but not by extra-gastrointestinal tissues and tumors. GC-C appears to be a sensitive and specific marker that can be employed to detect colorectal cancer cells in extra-intestinal sites. Preliminary studies demonstrated that GC-C RT-PCR could detect metastatic colorectal cancer cells in blood from all (34) patients examined with metastatic colorectal cancer. In addition, GC-C mRNA expression measured by RT-PCR detected occult micrometastases in lymph nodes that were free of disease by histopathology. Patients with lymph nodes positive for GC-C were at greater risk for cancer-related mortality compared to patients with lymph nodes that did not express GC-C These observations suggest that for patients undergoing post-operative surveillance for colorectal cancer, GC-C RT-PCR may be useful to detect micrometastases and recurrent disease earlier than other methods. This application will translate basic observations from our laboratory into new diagnostic tools for the management of colorectal cancer. In Specific Aim 1, GC-C expression will be examined in blood from control patients who do not have GI malignancies, with ages ranging from 40 yo to 90 yo, to establish the baseline value for GC-C RT-PCR in blood in the broad population of individuals at risk to develop colorectal cancer. In Specific Aim 2, the relationship between GC-C RT-PCR analysis in blood and metastatic colorectal cancer will be defined. It is expected that GC-C RT-PCR will be positive more often in the blood of patients with metastatic colorectal cancer compared to patients without metastatic disease. In Specific Aim 3, the temporal relationship between clinically evident recurrence and a positive GC-C RT-PCR will be compared to that of serum carcinoembryonic antigen (CEA) in serial blood samples collected prospectively from colorectal cancer patients undergoing post-operative surveillance. The prognostic value of GC-C RT-PCR will be compared to serum CEA levels in patients who recur during this study. It is anticipated that GC-C RT-PCR will be positive earlier and more frequently than CEA in the blood of patients who recur. The studies proposed will translate preliminary observations concerning the specificity of GC-C expression in human tissues and blood into clinical data which define the diagnostic utility of this novel marker for managing colorectal cancer patients during post-operative surveillance. These studies will form the foundation for future trials utilizing GC-C to identify patients at risk for recurrence who might benefit from therapeutic intervention.

描述（由申请人提供）：在美国，接受大肠癌“治愈”切除的患者中有50％患有复发性疾病。在某种程度上，这反映了缺乏在临床明显复发之前检测神秘微量转移的技术。 Guanylyl环化酶C（GC-C）由正常粘膜和结直肠癌细胞特异性表达，而不是通过肿瘤外的组织和肿瘤表达。 GC-C似乎是一种敏感且特异性的标记，可用于检测肠外部位中的结直肠癌细胞。初步研究表明，GC-C RT-PCR可以检测所有患有转移性结直肠癌的患者的血液中的结直肠癌细胞。此外，通过RT-PCR检测到的淋巴结中的隐匿性微量转移测量的GC-C mRNA表达在组织病理学中不含疾病的淋巴结中。与未表达GC-C的淋巴结患者相比，GC-C阳性淋巴结阳性的患者患癌症相关死亡率的风险更大与其他方法相比，-PCR可用于更早检测微转移和复发性疾病。该应用程序将将我们的实验室的基本观察结果转化为用于治疗结直肠癌的新诊断工具。在特定的目标1中，将在没有GI恶性肿瘤的对照患者的血液中检查GC-C表达，年龄从40 YO到90 YO，以确定GC-C-C RT-PCR的基线值大量的人群有生殖直肠癌的风险。在特定的目标2中，将定义血液中GC-C RT-PCR分析与转移性结直肠癌之间的关系。与没有转移性疾病的患者相比，预计GC-C RT-PCR在转移性结直肠癌患者的血液中会更阳性。在特定的目标3中，将比较临床明显复发与阳性GC-C RT-PCR之间的时间关系与从接受术后监测后结直肠癌患者收集的连续血样中的血清癌癌抗原（CEA）之间的时间关系。将GC-C RT-PCR的预后价值与本研究中复发的患者的血清CEA水平进行比较。预计在复发患者的血液中，GC-C RT-PCR比CEA更早，更频繁。提出的研究将转化有关人类组织中GC-C表达和血液特异性的初步观察，为临床数据，这些数据定义了这种新颖的标志物在术后监测过程中管理结直肠癌患者的诊断效用。这些研究将构成利用GC-C的未来试验的基础，以确定可能受益于治疗干预的患者。