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

细胞周期调节蛋白的异常表达是许多人类肿瘤的特征，包括肺癌 癌症。细胞周期蛋白 B1 (CB1) 的表达失调，通过组成型过度表达和 在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，这是肿瘤进展的早期事件 肺部恶性病变的癌前病变，表明它可能是肺部恶性病变的标志物和潜在靶点 早期和晚期癌症。肺癌中 CB1 过度表达会引发特异性抗体和 T 细胞。 CB1 特异性抗体也存在于罹患肺癌高风险的重度吸烟者中。 小鼠实验表明，抗 CB1 特异性免疫反应可以防止肿瘤攻击。的 项目 2 中要测试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，这将产生抗肿瘤作用。我们的第二个假设是 针对 CB1 的免疫反应可能是未来肺癌发展风险的生物标志物 有阳性吸烟史或新近复发的早期患者 诊断患有肺癌。这两个假设正在三个具体目标中得到检验。具体来说 目标 1 我们建议开展 I 期和 II 期临床试验，测试 CB1 疫苗的安全性和免疫原性 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 试图阐明保护的重要免疫相关性。在具体目标 3 中，我们建议评估 抗 CB1 抗体对高危个体和癌症患者的诊断和预后价值 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 翻译在过去的资助期内获得的有关 CB1 失调机制的新知识， 抗CB1免疫，对肺癌的诊断、预后和治疗。

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.