Charles Drew University/UCLA Cancer Center Partnership to Eliminate Cancer Health

查尔斯德鲁大学/加州大学洛杉矶分校癌症中心合作消除癌症健康

基本信息

批准号：
7943032
负责人：
Harold Phillip Koeffler
金额：
$ 95.08万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-29 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7943032
关键词：
African American Age Ambulatory Care American Cancer Society Arts Biological Breast Cancer Cell Cancer Center Cancer Patient Cancer Research Project Cancer cell line Caucasians Caucasoid Race Characteristics Charities Chemopreventive Agent Clinical Colorectal Data Death Rate Development Diagnosis Disease Dominant-Negative Mutation Drops Economically Deprived Population Ethnic group Future Genomics Goals Growth Health Healthy People 2010 Hispanics Immunohistochemistry Incidence Integrins Knowledge Latina Lead Learning Life Los Angeles Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mammary Gland Parenchyma Mammography Measures Medical Medical center Minority Monoclonal Antibodies Mus National Cancer Institute Outcome Paraffin Partner in relationship Pathogenesis Pathway interactions Patients Play Population Prognostic Marker Protein Binding Proteins RNA Race Reporting Research Personnel Resistance Role Running Sampling Science Screening procedure Services Staining method Stains Techniques Testing Therapeutic Time Tissue Microarray Transgenic Animals Transgenic Mice Transgenic Organisms Underrepresented Minority Underserved Population Universities Validation Woman cancer health disparity chemotherapy falls health disparity human FRAP1 protein in vivo insight malignant breast neoplasm men mortality novel novel therapeutic intervention novel therapeutics outcome forecast overexpression prognostic indicator programs receptor response statistics tumor progression

项目摘要

DESCRIPTION (provided by applicant): Relevance and Specific Aims Relevance: There is a critical need to understand the pathogenesis of breast cancer, in particular in minority and underserved populations who have poor survival. The purpose of this project is to develop a comprehensive breast cancer research project that provides the opportunity to identify novel biological targets for diagnosis and to follow progression of cancer in response to therapy in Minority and Underserved populations. We will accomplish our goal with the following specific aims: Specific Aim 1: Associate levels of CCN proteins and downstream targets in breast cancers with clinical parameters of the patients (Year 1). Breast cancer tissue arrays will be stained for CCN proteins and results will be correlated with ethnic grouping, especially African American and Hispanic populations, as well as their clinical information. This activity will be performed at CDU. Also, we have breast cancer cell line data that shows that CCN proteins bind to integrins and activate the (3-catenin/TCF and PI3K/AKT/mTOR/4EBP1/ SK6 pathways. Replicate breast cancer arrays will be stained to determine if these downstream proteins are activated in patient samples. We will use large tissue arrays from National Cancer Institute; validation will take advantage of large and well-characterized breast cancer paraffin blocks from Charities Drew University/ Martin Luther King Junior-MuIti Service Ambulatory Care Center (formerly known as the King-Drew Medical Center). This aim will demonstrate if there are biological differences between African American, Latina, and Caucasian breast cancer patients. To date, no one has associated level of expression of CCN proteins and ethnic group or other clinical characteristics of breast cancer. Our prior studies at the RNA level lead us to hypothesize that we will show by immunohistochemistry that levels of CCN proteins will be independent prognostic markers that foreshadow the aggressiveness of the disease. If we are correct, a simple immunohistochemical test for expression of CCN proteins can be performed at diagnosis to provide an indicator of prognosis and help direct the aggressiveness of therapy. Specific Aim 2: Study the effects of selective overexpression of CCN proteins in breast tissue of transgenic mice (Years 2-3). Transgenic mice that selectively overexpress CCN1 will be created to study the in vivo development of breast cancer. If cancers do not develop, these mice will be mated with mice that overexpress ErbB-2 (Her-2/neu). These mice should develop breast cancer at an earlier age than either transgenic alone. These mice can be used to test various chemopreventive, chemotherapeutic or other novel therapeutic strategies. Specific Aim 3: Identify domains of CCN1 and CCN2 necessary to enhance transformation of breast cancer cells (Years 1-2). Understanding the critical CCN motifs that enhance breast cancer growth will provide future targets for inhibiting breast cancer growth. Specific Aim 4 (Year 2-3): Explore the therapeutic implications of overexpression of CCN proteins in breast cancer. Taking advantage of the knowledge garnered in the preceding Specific Aims knowing that overexpression of CCN proteins make the breast cancer cells resistant to chemotherapy, we will try various therapeutic measures to block the CCN stimulatory pathways. Specific Aim 4A: Investigate the range, magnitude, and cause of chemo-resistance in CCN overexpressing breast cancer cells. Specific Aim 48: Inhibit the growth stimulating pathways in CCN expressing breast cancers. These approaches will include developing monoclonal antibodies that target CCN proteins and/or dominant negative proteins that block integrins (receptors of CCN proteins) or block the downstream pathways that are aberrantly stimulated by the CCN proteins. Taken together, the proposed studies will provide unique insights into the pivotal role that CCN proteins play in breast cancer especially in our minority served African American and Hispanic patients. These insights should lead to novel prognostic indicators of clinical outcome, as well as provide new therapeutic approaches to this devastating disease. The project offers outstanding opportunities for the CDU researchers to learn state of the art science and techniques in genomics in general, and specifically in the creation of transgenic animals. This project is run concurrently at CDU and Cedars/UCLA.

描述（由申请人提供）：相关性和具体目标相关性：迫切需要了解乳腺癌的发病机制，特别是在生存率较低的少数群体和服务不足的人群中。该项目的目的是开发一个全面的乳腺癌研究项目，为确定新的诊断生物学靶点提供机会，并跟踪少数民族和服务不足人群对治疗的反应的癌症进展。我们将通过以下具体目标来实现我们的目标：具体目标 1：将乳腺癌中 CCN 蛋白和下游靶标的水平与患者的临床参数相关联（第一年）。乳腺癌组织阵列将进行 CCN 蛋白染色，结果将与种族群体（尤其是非裔美国人和西班牙裔群体）及其临床信息相关。该活动将在 CDU 进行。此外，我们还有乳腺癌细胞系数据，显示 CCN 蛋白与整合素结合并激活 (3-连环蛋白/TCF 和 PI3K/AKT/mTOR/4EBP1/SK6 通路。复制的乳腺癌阵列将被染色以确定这些下游是否我们将使用国家癌症研究所的大型组织阵列来激活患者样本中的蛋白质；验证将利用德鲁大学/马丁慈善机构的大型且特征良好的乳腺癌石蜡块。路德金少年多功能服务流动护理中心（以前称为 King-Drew 医疗中心）该目标将证明非裔美国人、拉丁裔和白人乳腺癌患者之间是否存在生物学差异。迄今为止，还没有人将CCN蛋白的表达水平与乳腺癌的种族或其他临床特征相关联。我们之前在 RNA 水平上的研究使我们假设我们将通过免疫组织化学证明 CCN 蛋白水平将是预示疾病侵袭性的独立预后标志物。如果我们是正确的，则可以在诊断时对 CCN 蛋白的表达进行简单的免疫组织化学测试，以提供预后指标并帮助指导治疗的积极性。具体目标 2：研究转基因小鼠（2-3 岁）乳腺组织中 CCN 蛋白选择性过度表达的影响。将创建选择性过度表达 CCN1 的转基因小鼠来研究乳腺癌的体内发展。如果癌症没有发展，这些小鼠将与过度表达 ErbB-2 (Her-2/neu) 的小鼠交配。这些小鼠患乳腺癌的年龄应该比单独转基因的小鼠更早。这些小鼠可用于测试各种化学预防、化疗或其他新型治疗策略。具体目标 3：确定增强乳腺癌细胞转化所需的 CCN1 和 CCN2 结构域（1-2 年）。了解促进乳腺癌生长的关键 CCN 基序将为抑制乳腺癌生长提供未来的目标。具体目标 4（第 2-3 年）：探索 CCN 蛋白过度表达在乳腺癌中的治疗意义。利用在前面的具体目标中获得的知识，知道CCN蛋白的过度表达会使乳腺癌细胞对化疗产生抵抗力，我们将尝试各种治疗措施来阻断CCN刺激途径。具体目标 4A：研究 CCN 过表达乳腺癌细胞的化疗耐药性的范围、程度和原因。具体目标 48：抑制表达 CCN 的乳腺癌中的生长刺激途径。这些方法将包括开发针对 CCN 蛋白和/或显性失活蛋白的单克隆抗体，以阻断整合素（CCN 蛋白的受体）或阻断 CCN 蛋白异常刺激的下游途径。总而言之，拟议的研究将为 CCN 蛋白在乳腺癌中发挥的关键作用提供独特的见解，特别是在我们少数服务的非裔美国人和西班牙裔患者中。这些见解应该会产生新的临床结果预后指标，并为这种毁灭性疾病提供新的治疗方法。该项目为基民盟研究人员提供了绝佳的机会，让他们学习基因组学领域最先进的科学和技术，特别是转基因动物的创造。该项目在基民盟和雪松/加州大学洛杉矶分校同时运行。