CYCLIN B1 IN IMMUNOTHERAPY, DIAGNOSIS, AND PROGNOSIS OF LUNG CANCER

细胞周期蛋白 B1 在肺癌免疫治疗、诊断和预后中的作用

• 批准号: 7088494
• 负责人: Olivera J Finn
• 金额: $ 20.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088494
• 关键词: antibody; cyclins; immunotherapy; lung; neoplasm /cancer

Aberrant expression of cell cycle regulatory proteins characterizes many human tumors, including lung cancer. Dysregulated expression of cyclin B1 (CB1), demonstrated by constitutive overexpression and mislocalization in the cytoplasm rather than the nucleus, is especially significant because it contributes to malignant transformation and increased metastatic potential of tumor cells. Aberrant expression of CB1 is a result of functional inactivation of the tumor suppressor gene p53, an early event in the progression from premalignant to malignant lesions in the lung, suggesting that it could be a marker and a potential target in early as well as late stage cancer. CB1 overexprression in lung cancer elicits specific antibodies and T cells. CB1-specific antibodies are also seen in heavy smokers who are at high risk for developing lung cancer. Experiments, in mice show that anti-CB1 specific immune responses can protect from tumor challenge. The first hypothesis to be tested in Project 2 is that vaccines will elicit or boost CB1-specific immunity in lung cancer patients and that will result in an anti-tumor effect. Our second hypothesis is that the immune response against CB1 could be a biomarker of risk for development of future lung cancer in subjects with a positive smoking history or for recurrence among early-stage patients newly diagnosed with lung cancer. These two hypotheses are being tested in three specific aims. In Specific Aim 1 we propose to carry out clinical trials testing CB1 vaccines safety and immunogenicity in stage I and II lung cancer patients undergoing tumor resection. In Specific Aim 2 we will analyze and compare the quantitative and qualitative features of anti-cyclin B1 immunity in cancer patients and high-risk individuals in an attempt to elucidate important immune correlates of protection. In Specific Aim 3 we propose to evaluate the diagnostic and prognostic value of anti-CB1 antibodies in high risk individuals and cancer patients and to compare it to other diagnostic and prognostic markers studied in the SPORE projects. The overall goal is to translate the new knowledge acquired in the past grant period on the mechanisms of CB1 dysregulation and anti-CB1 immunity, to diagnosis, prognosis and therapy of lung cancer.

细胞周期调节蛋白的异常表达表征了许多人类肿瘤，包括肺 癌症。细胞周期蛋白B1（CB1）的表达失调，由本构的过表达和 细胞质而不是细胞核中的错误定位尤其重要，因为它有助于 恶性转化和肿瘤细胞的转移潜力增加。 CB1的异常表达是 肿瘤抑制基因p53功能失活的结果，这是从 对肺部恶性病变过敏性，这表明它可能是标记和潜在的靶标 早期和晚期癌症。肺癌中的CB1发作会引起特定的抗体和T细胞。 在患有肺癌的高风险的浓烟中，也可以看到CB1特异性抗体。 实验中，在小鼠中表明抗CB1特异性免疫反应可以防止肿瘤挑战。这 在项目2中要检验的第一个假设是疫苗将引起或增强CB1特异性免疫力 肺癌患者，这将导致抗肿瘤作用。我们的第二个假设是 对CB1的免疫反应可能是出现未来肺癌发展风险的生物标志物 新阶段患者的吸烟病史或重复发生的受试者 被诊断为肺癌。这两个假设正在以三个特定目标进行检验。具体 AIM 1我们建议在I和II中进行CB1疫苗安全性和免疫原性测试临床试验 肺癌患者接受肿瘤切除。在特定目标2中，我们将分析和比较 癌症患者和高风险个体抗周期蛋白B1免疫的定量和定性特征 试图阐明重要的免疫相关性。在特定目标3中，我们建议评估 高风险个体和癌症患者的抗CB1抗体的诊断和预后价值以及 将其与孢子项目中研究的其他诊断和预后标记进行比较。总体目标是 翻译有关CB1失调机制和 抗CB1免疫，以诊断，预后和肺癌治疗。