Targeting y-secretase in breast cancer

三阴性乳腺癌约占浸润性乳腺癌的15%， 对非裔美国人和年轻女性的影响不成比例。这些患者复发的风险很高。 和转移。治疗选择仍然有限，迫切需要新的靶向制剂。我们和 其他研究表明，γ-分泌酶抑制物(GSI)在乳腺癌临床前模型中是活跃的，包括 TNBC。GSIS正在TNBC中进行测试，基于Notch和其他γ-分泌酶底物发挥作用的概念 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危及临床 跨国公司地理信息系统的发展。该项目将检验这样的假设：a)GSI影响肿瘤生长 直接和通过这类药物之间不同的肿瘤宿主效应；以及B)GSI的作用 至少部分是通过与血管内皮生长因子和AKT通路的相互作用来调节的。我们的数据显示，GSI 它们对TNBC细胞、内皮细胞和T细胞的作用在质量和效力上有所不同。根本没有 GSI抑制规范Notch靶基因HES1表达的能力与其表达的明显相关性 体外或患者体内的生物活性。GSIS与酪氨酸激酶有显著的药理相互作用 抑制剂舒尼替尼和AKT抑制剂Perifosine。GSI-Perifosine组合在TNBC中更活跃 异种移植比单独使用任何一种药物都要好。GSI抑制在肿瘤中起关键作用的Th17 T辅助反应 发育和血管生成。我们计划比较几种调查性的GSI，包括凹槽保留 和Notch选择性药物相互作用，并直接指向Notch抑制剂，如显性负性MAML1 TNBC细胞、内皮细胞和T细胞中的多肽。我们将探索选定的地理标志的影响，单独和 与舒尼替尼或Perifosine联合使用，对肿瘤血管生成和T辅助细胞反应的影响 TNBC转基因小鼠模型的建立。我们将确定抗肿瘤活性的候选生物标记物进行测试 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。

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.