Targeted Intervention of Breast Oncogenic Pathways

乳腺致癌途径的靶向干预

基本信息

批准号：
7435730
负责人：
SAID M SEBTI
金额：
$ 12.15万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-06-13 至 2008-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7435730
关键词：
Address Adriamycin PFS Agar Albert Einstein Cancer Center Antibodies Antineoplastic Agents Apoptosis Biochemical Biological Assay Biopsy Breast Breast Cancer Cell Breast Cancer Treatment Cancer Patient Cancer cell line Cantor Chemicals Cities Clinical Clinical Trials Comprehensive Cancer Center Cyclophosphamide Cytotoxic agent Disruption Doctor of Medicine Doctor of Philosophy Dominant-Negative Mutation Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ErbB4 gene Face Family member Farnesyl Transferase Inhibitor Florida Gefitinib Genetic Goals Her2/erbb2/neu Staining Method Heterodimerization Homodimerization Human Immunohistochemistry Instruction Intervention Janus kinase Ligands MEKs Malignant - descriptor Mammary Neoplasms Measurement Medical center Molecular Names Nude Mice Numbers Oncogenic Pathologist Pathway interactions Patients Phase Phase I Clinical Trials Principal Investigator Printing Protein Farnesylation Protein Overexpression Protein Tyrosine Kinase Proteins R115777 (Zarnestra)Receptor Protein-Tyrosine Kinases Research Project Grants Resistance Roche brand of trastuzumab Role STAT3 gene Signal Pathway Signal Transduction Signal Transduction Pathway Testing Treatment outcome Universities Xenograft procedure cancer cell chemotherapy cytotoxic design docetaxel farnesyltranstransferase improved inhibitor/antagonist malignant breast neoplasm medical schools outcome forecast programs protein farnesyltransferase receptor response tumor tumorigenesis

项目摘要

The overall goal of this project is to understand the role of the oncogenic and tumor survival pathways, Mek/Erk, JAK/STAT3 and PI3K/Akt in breast oncogenesis and to develop new strategies for more effective breast cancer treatment. The receptor tyrosine kinase ErbB2 is overexpressed in human breast cancer and this is associated with poor prognosis. ErbB2 heterodimerizes with ErbB 1(EGFR), ErbB3 or ErbB4 and stimulates many signal transduction pathways leading to the constitutively activated Akt, STAT3 and Erkl/2 in breast cancer. It remains, however, unclear which of these pathways are most important for maintaining malignant transformation. Furthermore, the contribution of Mek/Erk, JAK/STAT3 and PI3K/Akt pathways to breast oncogenesis and treatment outcome is not known. We and others have developed disrupters of these signaling pathways including antibodies to ErbB2 and inhibitors of ErbB 1 tyrosine kinase, Mek and PI3K kinases, JAK/STAT3 signaling and farnesyltransferase, an enzyme required for the activation of famesylated proteins such as Ras which activates Mek/Erk and PI3K/Akt pathways. In this project we propose to test the hypothesis that constitutively activated Mek/Erk, JAK/STAT3 and/or PI3K/Akt pathways contribute to breast oncogenesis and tumor resistance, and that targeted intervention of these pathways blocks malignant transformation, induces apoptosis and sensitizes breast tumors to chemotherapy. This hypothesis will be tested through the following specific aims: 1) To investigate the role of constitutively activated PI3K/Akt, JAK/STAT3 and Mek/Erk, in breast cancer oncogenesis. Here we will determine if genetic and pharmacological disruptions of these pathways reverse malignant transformation arid induce apoptosis. Dominant negative forms of PI3K, Akt, Mek, STAT3 and Ras will be used. Phamlacological inhibitors of JAK/STAT3 pathway, PI3K, Mek and famesyltransferase will also be used individually or in combination. 2) To determine if resistance to Herceptin or Iressa of ErbB2 and/or EGFR overexpressing breast cancer cells is due to constitutively activated Akt/PI3K, JAK/STAT3 and/or MEK/Erk pathways. To this end, we will determine if inhibitors of these pathways sensitize breast cancer cells to Herceptin and/or Iressa. 3) To determine if resistance of breast cancer cells to Adriamycin, cyclophosphamide and/or taxotere could be overcome by targeted pharmacological intervention of PI3K/Akt, Mek/Erk and/or JAK/STAT3 pathways. 4) To conduct a hypothesis-driven phase I/lI clinical trial of preoperative Adriamycin (A), cyclophosphamide (C) and FTI R115777 (Zarnestra) in patients with locally advanced breast cancer and metastatic breast cancer. Here we will determine if pre-treatment levels of ErbB 1, ErbB2, ErbB3 and/or ErbB4, and phosphorylated levels of Akt, STAT3 and/or Erkl/2 predict clinical response to AC/FTI. We will also correlate clinical response to ability to suppress protein famesylation and the levels ofphospho Akt, phospho Erkl/2 and/or phospho STAT3. Results from these studies will enhance our understanding of the role of Mek/Erk, JAK/STAT3 and PI3K/Akt pathways in breast cancer oncogenesis and treatment outcome and will result in improved therapies of human breast cancers. PERFORMANCESITE(S) (organization,city,state) H. Lee Moffitt Comprehensive Cancer Center Albert Einstein Comprehensive Cancer Center University of South Florida School of Medicine and Montefiore Medical Center Tampa, FL 33621 Bronx, NY KEYPERSONNEL.See instructions.Usecontinuationpagesas neededto providethe requiredinformationin the formatshownbelow. StartwithPrincipalInvestigatorListall otherkeypersonnelinalphabeticaol rder,lastnamefirst. Name Organization Roleon Project Said M. Sebti, Ph.D. University of South Florida Principal Investigator Joseph Sparano, M.D. Albert Einstein Cancer Center Co-Principal Investigator Nils Diaz, M.D. University of South Florida Collaborator (Molecular Pathologist) Alan Cantor, Ph.D. University of South Florida Collaborator (Biostatistician) Disc/osurePermission Statement. Applicableto SBIPJS'I-rROnly. See instructions.[] Yes [] No o PHS398(Rev,05/01) Page2 FormPage2 [] o Principal Investigator/Program Director (Last, first, middle): Sebti, Safd M. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT "TARGETED INTERVENTION OF BREAST ONCOGENIC PATHWAYS" TABLE OF CONTENTS Page Numbers Face Page .................................................................................................................................................. 1 Description,

该项目的总体目标是了解致癌和肿瘤生存途径 Mek/Erk、JAK/STAT3 和 PI3K/Akt 在乳腺癌发生中的作用，并开发更有效乳腺癌治疗的新策略。酪氨酸受体激酶 ErbB2 在人类乳腺癌中过度表达，这与不良预后相关。 ErbB2 异二聚化 ErbB 1(EGFR)、ErbB3 或 ErbB4 并刺激许多信号转导途径，导致持续激活 Akt，乳腺癌中的 STAT3 和 Erkl/2。然而，目前尚不清楚这些途径中哪一条对于维持恶变。此外，Mek/Erk、JAK/STAT3 和 PI3K/Akt 通路对乳腺肿瘤发生的贡献治疗结果尚不清楚。我们和其他人已经开发出这些信号通路的破坏者，包括抗体 ErbB2 和 ErbB 1 酪氨酸激酶、Mek 和 PI3K 激酶、JAK/STAT3 信号传导和法尼基转移酶（一种酶）的抑制剂法尼基化蛋白（如 Ras）激活所需，可激活 Mek/Erk 和 PI3K/Akt 通路。在这个项目中我们建议测试以下假设：组成型激活的 Mek/Erk、JAK/STAT3 和/或 PI3K/Akt 通路有助于乳腺肿瘤发生和肿瘤抵抗，并且有针对性地干预这些途径可以阻止恶性转化，诱导细胞凋亡并使乳腺肿瘤对化疗敏感。该假设将通过具体目标如下： 1) 研究组成型激活的 PI3K/Akt、JAK/STAT3 和 Mek/Erk 在乳腺中的作用癌症发生。在这里，我们将确定这些途径的遗传和药理学破坏是否可以逆转恶性转化并诱导细胞凋亡。将使用 PI3K、Akt、Mek、STAT3 和 Ras 的显性阴性形式。药理学 JAK/STAT3途径抑制剂、PI3K、Mek和法呢基转移酶也将单独或联合使用。 2) 至确定 ErbB2 和/或 EGFR 过表达乳腺癌细胞对赫赛汀或易瑞沙的耐药性是否是由于组成型所致激活 Akt/PI3K、JAK/STAT3 和/或 MEK/Erk 通路。为此，我们将确定这些途径的抑制剂是否使乳腺癌细胞对赫赛汀和/或易瑞沙敏感。 3) 确定乳腺癌细胞是否对阿霉素产生耐药性，环磷酰胺和/或泰索帝可以通过 PI3K/Akt、Mek/Erk 和/或的靶向药物干预来克服 JAK/STAT3 途径。 4) 进行一项假设驱动的术前阿霉素 I/lI 期临床试验 (A)，环磷酰胺 (C) 和 FTI R115777 (Zarnestra) 用于局部晚期乳腺癌和转移性乳腺癌患者。在这里，我们将确定治疗前 ErbB 1、ErbB2、ErbB3 和/或 ErbB4 的水平以及 Akt、STAT3 的磷酸化水平和/或Erkl/2预测对AC/FTI的临床反应。我们还将临床反应与抑制蛋白质的能力联系起来法磺基化和磷酸化Akt、磷酸化Erk1/2和/或磷酸化STAT3的水平。这些研究的结果将增强我们的了解 Mek/Erk、JAK/STAT3 和 PI3K/Akt 通路在乳腺癌肿瘤发生和治疗结果中的作用并将改善人类乳腺癌的治疗方法。表演地点（组织、城市、州） H. Lee Moffitt 综合癌症中心艾伯特·爱因斯坦综合癌症中心南佛罗里达大学医学院和蒙蒂菲奥里医疗中心坦帕, FL 33621 布朗克斯, 纽约关键人员。请参阅说明。根据需要使用续页以如下所示的格式提供所需信息。从主要研究者开始，按字母顺序列出所有其他关键人员，姓氏在前。名称组织 Roleon 项目 M. Sebti 博士说道。南佛罗里达大学首席研究员 Joseph Sparano，医学博士阿尔伯特·爱因斯坦癌症中心联合首席研究员 Nils Diaz，医学博士南佛罗里达大学合作者（分子病理学家）艾伦·坎托博士南佛罗里达大学合作者（生物统计学家） Disc/osure 许可声明。仅适用于 SBIPJS'I-rR。请参阅说明。[] 是 [] 否 o PHS398(Rev,05/01) 第 2 页表格第 2 页 [] o 首席研究员/项目总监（最后、第一、中间）：Sebti, Safd M. 首席研究员/项目主管的姓名必须在每个打印页和每个续页的顶部提供。研究资助 “乳腺致癌途径的针对性干预” 目录页码面页................................................ ...................................................... ...................................................... 1 描述，