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) 约占浸润性乳腺癌的 15% 对非裔美国人和年轻女性的影响尤为严重。这些患者复发风险较高和转移。治疗选择仍然有限，迫切需要新的靶向药物。我们和其他研究表明，γ-分泌酶抑制剂 (GSI) 在乳腺癌临床前模型中具有活性，包括 TNBC。基于 Notch 和其他 y 分泌酶底物发挥作用的概念，GSI 正在 TNBC 中进行测试在乳腺癌生物学中发挥重要作用。然而，关键的知识差距可能会影响临床 TNBC 中 GSI 的发展。该项目将检验以下假设： A) GSI 影响肿瘤生长直接或通过肿瘤宿主效应，此类药物之间存在差异； B) GSI 的影响至少部分是通过与 VEGF 和 AKT 通路的串扰介导的。我们的数据显示，GSI 它们对 TNBC 细胞、内皮细胞和 T 细胞的作用质量和效力有所不同。没有 GSI 抑制典型 Notch 目标 HES1 表达的能力与其体外或患者体内的生物活性。 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 抑制剂哌立福辛。 GSI-哌立福辛组合在 TNBC 中更有效异种移植效果优于单独使用任何一种药物。 GSI 抑制 Th17 T 辅助细胞反应，这在肿瘤中发挥着至关重要的作用发育和血管生成。我们计划比较几个研究中的 GSI，包括 Notch-sparing 和Notch选择性药物彼此相互作用并指导Notch抑制剂，例如显性失活MAML1 TNBC 细胞、内皮细胞和 T 细胞中的肽。我们将单独探讨选定的 GSI 的影响与舒尼替尼或哌立福辛联合使用，可改善肿瘤中的血管生成和 T 辅助细胞反应，使用一种新型药物 TNBC转基因小鼠模型。我们将确定待测试的抗肿瘤活性候选生物标志物诊所。最后，我们将探讨Notch介导的AKT激活在GSI的抗肿瘤活性中的作用在TNBC。