Targeting y-secretase in breast cancer

靶向乳腺癌中的γ分泌酶

基本信息

批准号：
8415151
负责人：
Lucio Miele
金额：
$ 36.23万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415151
关键词：
Accounting Adoptive Transfer Affect Affinity African American Aftercare Antineoplastic Agents Biological Biological Markers Breast Cancer Cell CCL2 gene Cancer Biology Cancer Model Cancer cell line Cells Clinic Clinical Clinical Trials Communities Data Development Disease Dominant-Negative Mutation ES01 Endothelial Cells Event Gene Expression Genotype Goals Human IL8 gene Immune Immunocompetent In Vitro Individual Instruction Interleukin-17 Interleukin-6 Knock-out Knockout Mice Knowledge Ligands Literature Lymphocyte Lymphocytic Infiltrate Malignant Neoplasms Mammary gland Measures Mediating Molecular Molecular Profiling Mus Neoplasm Metastasis Oncology PTEN gene Pathway interactions Patients Peptides Perifosine Pharmaceutical Preparations Pharmacologic Substance Play Pre-Clinical Model Proto-Oncogene Proteins c-akt RANTES Recruitment Activity Recurrence Regulatory T-Lymphocyte Reporting Role Signal Transduction T-Lymphocyte Testing Therapeutic Transgenic Mice Translating Tyrosine Kinase Inhibitor Vascular Endothelial Growth Factors Writing Xenograft procedure angiogenesis antiangiogenesis therapy base cancer cell density design gamma secretase high risk host neoplasm interaction in vitro activity in vivo inhibitor/antagonist interleukin-22 interleukin-23 macrophage malignant breast neoplasm mouse model neoplastic neoplastic cell notch protein novel paralogous gene research study response secretase triple-negative invasive breast carcinoma tumor tumor growth willingness young woman

项目摘要

Triple-negative breast cancer (TNBC) accounts for approximately 15% of invasive breast cancers and disproportionately affects African-American and younger women. These patients have high risk of recurrence and metastasis. Treatment options remain limited and new targeted agents are urgently needed. We and others have shown that y-secretase inhibitors (GSI) are active in breast cancer preclinical models, including TNBC. GSIs are being tested in TNBC based on the notion that Notch and other y-secretase substrates play important roles in breast cancer biology. However, critical knowledge gaps may compromise the clinical development of GSIs in TNBC. This project will test the hypothesis that: A) GSIs affect tumor growth both directly and through tumor host effects that vary between the drugs in this class; and B) the effects of GSIs are at least in part mediated through cross-talk with the VEGF and AKT pathways. Our data show that GSIs differ in the quality and potency of their effects on TNBC cells, endothelial cells and T-cells. There was no obvious correlation between the ability of GSIs to inhibit expression of canonical Notch target HES1 and their biological activity in vitro or in patients. GSIs have significant pharmacologic interactions with tyrosine kinase inhibitor sunitinib and AKT inhibitor perifosine. A GSI-perifosine combination is more active in TNBC xenografts than either drug alone. GSI inhibit Th17 T-helper responses, which play a crucial role in tumor development and angiogenesis. We plan to compare several investigational GSIs including Notch-sparing and Notch-selective agents to each other and to direct Notch inhibitors such as dominant negative MAML1 peptides in TNBC cells, endothelial cells and T-cells. We will explore the effects of selected GSIs, alone and in combination with sunitinib or perifosine, on angiogenesis and T-helper responses in tumors, using a novel transgenic mouse model of TNBC. We will identify candidate biomarkers of anti-tumor activity to be tested in the clinic. Finally, we will explore the role of Notch-mediated AKT activation in the anti-tumor activity of GSIs in TNBC.

三阴性乳腺癌（TNBC）约占浸润性乳腺癌和不成比例地影响非裔美国人和年轻妇女。这些患者复发的风险很高和转移。治疗方案仍然有限，迫切需要新的靶向代理。我们和其他人则表明，Y-分泌酶抑制剂（GSI）在乳腺癌临床前模型中活跃，包括 TNBC。基于Notch和其他Y-分泌酶基板播放的概念，正在TNBC中测试GSI 在乳腺癌生物学中的重要作用。但是，关键的知识差距可能会损害临床 TNBC中GSI的开发。该项目将检验以下假设：a）GSI都会影响肿瘤生长直接并通过该类别药物之间有所不同的肿瘤宿主作用； b）GSI的影响至少部分通过与VEGF和AKT途径的串扰介导。我们的数据显示GSIS 它们对TNBC细胞，内皮细胞和T细胞的影响的质量和效力不同。没有 GSI抑制规范Notch靶标Hes1及其其表达的能力之间的明显相关性体外或患者的生物活性。 GSI与酪氨酸激酶具有显着的药理相互作用抑制剂舒尼替尼和Akt抑制剂perifosine。 GSI-prifosine组合在TNBC中更为活跃异种移植物比单独使用任何一种药物。 GSI抑制Th17 t-辅助反应，在肿瘤中起着至关重要的作用发育和血管生成。我们计划比较几个调查GSI，包括缺口和缺口选择剂相互互相指导，并指导Notch抑制剂（例如显性负MAML1） TNBC细胞，内皮细胞和T细胞中的肽。我们将单独探索选定的GSI的影响结合舒尼替尼或perifosine，使用新型 TNBC的转基因小鼠模型。我们将确定要测试的抗肿瘤活性的候选生物标志物诊所。最后，我们将探讨Notch介导的Akt激活在GSIS抗肿瘤活性中的作用在TNBC中。