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。