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

P2 - 细胞周期蛋白 B1 在肺癌免疫治疗、诊断和预后中的作用

基本信息

批准号：
8092831
负责人：
Olivera J Finn
金额：
$ 31.86万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8092831
关键词：
Adjuvant Adverse reactions Affinity Antibodies Antigens Aromatase Biological Assay Biological Markers Biological Response Modifier Therapy Blood Breast Breast Melanoma CD8B1 gene Cancer Etiology Cancer Patient Cancer Vaccines Cause of Death Cell Cycle Proteins Cell Nucleus Cessation of life Clinical Clinical Trials Colon Cytoplasm Cytotoxic agent Data Data Analyses Data Set Dendritic Cells Detection Development Diagnosis Diagnostic Diagnostic Neoplasm Staging Diagnostic Procedure Disease Effectiveness Enzyme-Linked Immunosorbent Assay Epidermal Growth Factor Receptor Epitopes Estrogen Receptors Event Excision Future Goals Grant HLA-A2 Antigen Human Immune Immune response Immune system Immunity Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin M Immunotherapy Individual Knowledge Lesion Localized Disease Longterm Follow-up Lung Lung Neoplasms Lung nodule Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Measures Mediating Memory Metastatic to Methods Molecular Monitor Monitoring for Recurrence Mus Newly Diagnosed Non-Small-Cell Lung Carcinoma Normal tissue morphology Outcome Participant Patients Peptide Library Peptides Phase Phenotype Pilot Projects Plasma Population Premalignant Preneoplastic Change Process Production Prognostic Marker Progress Reports Proteins Recombinants Recording of previous events Recurrence Regulatory T-Lymphocyte Relative (related person)Reporting Reproduction spores Resectable Resected Risk Screening Result Smoker Smoking History Specificity Staging Staining method Stains Surrogate Endpoint T-Lymphocyte TP53 Gene Inactivation Testing Th2 Cells Time Tissues Toxic effect Translating Tumor Antigens Vaccinated Vaccination Vaccines Validation base cohort cyclin B1 cytokine design enzyme linked immunospot assay high risk immunogenicity long term memory lung cancer screening neglect neoplastic cell novel novel therapeutics outcome forecast overexpression patient population prevent prognostic prognostic indicator protein expression prototype research study response statistics tumor tumor specificity vaccine efficacy vaccine safety

项目摘要

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。这项目 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。