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是包括肺癌在内的许多人类肿瘤的特征 癌症。细胞周期蛋白B1(CB1)的异常表达，表现为结构性过表达和 在细胞质而不是在细胞核中的错误定位尤其重要，因为它有助于 肿瘤细胞的恶性转化和转移潜能增加。CB1的异常表达是一种 肿瘤抑制基因P53功能失活的结果，这是从 肺内癌前病变到恶性病变，提示它可能是一种标志物和潜在的靶点 无论是早期癌症还是晚期癌症。肺癌中CB1的过度表达可引起特异性抗体和T细胞。 CB1特异性抗体也出现在重度吸烟者身上，他们患肺癌的风险很高。 在小鼠身上的实验表明，抗CB1特异性免疫反应可以保护小鼠免受肿瘤的攻击。这个 将在项目2中测试的第一个假设是，疫苗将诱导或增强CB1特异性免疫 对肺癌患者来说，这会产生抗肿瘤的作用。我们的第二个假设是 针对CB1的免疫反应可能是未来发生肺癌的风险的生物标志物 有阳性吸烟史或早期患者复发的受试者 被诊断出患有肺癌。这两个假说正在三个具体目标上接受检验。具体而言 目的1我们建议在第一和第二阶段进行临床试验，测试CB1疫苗的安全性和免疫原性。 接受肿瘤切除的肺癌患者。在具体目标2中，我们将分析和比较 新疆癌症患者及高危人群抗细胞周期蛋白B1免疫的定量和定性特征 试图阐明重要的免疫保护相关因素。在具体目标3中，我们建议评估 抗CB1抗体在高危人群和癌症患者中的诊断和预后价值 将其与孢子项目中研究的其他诊断和预后标记物进行比较。总体目标是 翻译在过去的授权期中获得的关于CB1失调机制和 抗CB1免疫，对肺癌的诊断、预后和治疗具有重要意义。