Targeting y-secretase in breast cancer

三阴性乳腺癌（TNBC）约占浸润性乳腺癌的15%， 对非洲裔美国人和年轻女性的影响尤为严重。这些患者复发风险高 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γ-分泌酶底物在TNBC中发挥作用的概念， 在乳腺癌生物学中的重要作用。然而，关键的知识差距可能会损害临床 在TNBC中开发GSI。本项目将检验以下假设：A）GSI影响肿瘤生长， 直接和通过肿瘤宿主作用，这类药物之间存在差异;和B）GSI的作用 至少部分是通过与VEGF和AKT途径的交叉作用介导的。我们的数据显示， 它们对TNBC细胞、内皮细胞和T细胞的作用的质量和效力不同。没有 GSI抑制经典Notch靶点HES 1表达的能力与它们的表达之间存在明显的相关性。 体外或患者体内的生物活性。GSI与酪氨酸激酶具有显著的药理学相互作用 抑制剂舒尼替尼和AKT抑制剂哌立福新。GSI-哌立福新组合在TNBC中更有活性 异种移植物的效果更好。GSI抑制Th 17辅助性T细胞反应，其在肿瘤中起关键作用 发育和血管生成。我们计划比较几种研究性GSI，包括Notch-sparing 和Notch-选择性试剂相互作用，并指导Notch抑制剂，如显性负性MAML 1 TNBC细胞、内皮细胞和T细胞中的肽。我们将探讨选定的GSI的影响，单独和 与舒尼替尼或哌立福新联合，对肿瘤血管生成和辅助性T细胞应答的影响， TNBC的转基因小鼠模型。我们将确定候选的抗肿瘤活性的生物标志物，以进行测试， 诊所最后，我们将探讨Notch介导的AKT激活在GSI抗肿瘤活性中的作用 在TNBC。

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.