P2 - CYCLIN B1 IN IMMUNOTHERAPY, DIAGNOSIS, AND PROGNOSIS OF LUNG CANCER

细胞周期调控蛋白的异常表达是许多人类肿瘤的特征，包括肺肿瘤， 癌细胞周期蛋白B1（CB1）表达失调，表现为组成性过表达， 在细胞质而不是细胞核中的错误定位，特别重要，因为它有助于 恶性转化和肿瘤细胞转移潜能增加。CB1的异常表达是 肿瘤抑制基因p53功能失活的结果，这是肿瘤进展的早期事件， 肺的癌前病变到恶性病变，这表明它可能是一个标志物和潜在的目标， 早期和晚期癌症。CB1在肺癌中的过表达激发特异性抗体和T细胞。 CB1特异性抗体也见于重度吸烟者中，这些人患肺癌的风险很高。 在小鼠中的实验表明，抗CB1特异性免疫应答可以保护免受肿瘤攻击。的 在项目2中要检验的第一个假设是，疫苗将引发或增强CB1特异性免疫， 肺癌患者，这将导致抗肿瘤效果。我们的第二个假设是 对CB1的免疫应答可能是未来肺癌发展风险的生物标志物， 有阳性吸烟史的受试者或新发早期患者中的复发受试者 被诊断为肺癌这两个假设正在三个具体目标中得到检验。在特定 目的1：我们建议在第I和第II阶段进行CB1疫苗安全性和免疫原性的临床试验 接受肿瘤切除术的肺癌患者。在具体目标2中，我们将分析和比较 癌症患者和高风险个体抗细胞周期蛋白B1免疫的定量和定性特征 试图阐明重要的免疫保护相关性。在具体目标3中，我们建议评估 抗CB1抗体在高风险个体和癌症患者中的诊断和预后价值， 将其与SPORE项目中研究的其他诊断和预后标志物进行比较。总体目标是 翻译在过去的赠款期间获得的关于CB1失调机制的新知识， 抗CB1免疫对肺癌的诊断、预后及治疗的意义。

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.