Abstract 5072: Targeting the mTOR/TORC Pathway for the prevention of er-negative and triple-negative breast cancer

A. Mazumdar, Jamal L Hill, Yun Zhang, L. Bollu, A. Contreras, Michelle I Savage, S. Sei, Altaf Mohammed, P. Brown
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引用次数: 0

Abstract

Background: Women with “triple-negative breast cancer” (TNBC), are currently treated with chemotherapy, and have a very poor prognosis. TNBC tumors also frequently have p53 and BRCA1 gene mutations. Dysregulation of PI3K-mTOR pathway has been commonly associated with ER-negative breast cancers with poor prognosis. The mTOR inhibitor everolimus is used to treat ER-positive tumors that have become resistant to anti-estrogen therapy. We hypothesized that targeting mTOR may prevent development of ER-negative and BRCA1-mutant breast cancers and asked whether the mTOR inhibitor everolimus exhibited tumor preventive efficacy in several mouse models of breast cancer. Methods: p53-null mammary gland donor mice were transplanted into cleared fat pads of p53 wild-type mice. BRCA/p53-deficient mice: We produced BRCA1 mice by breeding males and females. All mice were separated into two groups 1) Control and 2) everolimus. MMTV-erbB2 and p53 null mammary gland mice were treated with everolimus (5mg/kg, by oral gavage). BRACA1 mice were given 2mg/kg and 5mg/kg 2X a week of everolimus. All of these mice spontaneously developed mammary tumors within 12 months. Mice were observed daily, toxicity and the percentage of tumor free mice were recorded. Tumor incidence and time to tumor formation was visualized using Kaplan- Meier curves and analyzed using the generalized Wilcoxon test. Results: In MMTV-erbB2 mice everolimus reduced tumor incidence and was associated with an increase in median survival time from 240 days to 410 days. At 365 days, when all mice in control group died, only half of the mice treated with everolimus had developed tumors (p=0.0001). Everolimus also reduced tumor incidence in p53 null mammary gland mice. At 420 days, 50% of the control mice developed mammary tumors compare to only 7 % of the everolimus treated mice (p=0.04). Everolimus also reduced tumor incidence in BRCA1 mice. At 262 days, when 13 (out of 18) (72%) of the control mice developed mammary tumors compare to only 7 (out of 18) (38%) in everolimus treated group developed tumors (p=0.02). Long term treatment (>150 days) of everolimus was associated with mild toxicity that includes slight weight loss ( Conclusions: The mTOR inhibitor everolimus prevented mammary tumorigenesis in all three mouse models. Our results suggest that everolimus can be an effective cancer preventive drug and that further studies with reduced everolimus dose alone or in combination with other targeted therapies are warranted. In the future, clinical trials of the everolimus should be considered for the prevention of breast cancer in high-risk patients. Supported by NCI PREVENT Cancer Preclinical Drug Development Program (HHSN-2612015000-18I (PB)). Citation Format: Abhijit Mazumdar, Jamal Hill, Yun Zhang, Lakshmi Reddy Bollu, Alejandro Contreras, Michelle Savage, Shizuko Sei, Altaf Mohammed, Powel Brown. Targeting the mTOR/TORC Pathway for the prevention of er-negative and triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5072.
摘要5072:靶向mTOR/TORC通路预防er阴性和三阴性乳腺癌
背景:女性“三阴性乳腺癌”(TNBC)目前接受化疗,预后非常差。TNBC肿瘤也经常有p53和BRCA1基因突变。PI3K-mTOR通路失调通常与预后不良的er阴性乳腺癌相关。mTOR抑制剂依维莫司用于治疗对抗雌激素治疗产生耐药性的er阳性肿瘤。我们假设靶向mTOR可以预防er阴性和brca1突变乳腺癌的发展,并询问mTOR抑制剂依维莫司是否在几种乳腺癌小鼠模型中表现出肿瘤预防功效。方法:将p53缺失的乳腺供体小鼠移植到p53野生型小鼠清除的脂肪垫中。BRCA/p53缺陷小鼠:我们通过雄性和雌性繁殖产生BRCA1小鼠。所有小鼠分为两组:对照组和依维莫司组。以依维莫司(5mg/kg,灌胃)治疗MMTV-erbB2和p53缺失乳腺小鼠。BRACA1小鼠给予依维莫司2mg/kg和5mg/kg每周2次。所有这些小鼠在12个月内自发地产生了乳腺肿瘤。每天观察小鼠,记录毒性和无瘤小鼠百分比。使用Kaplan- Meier曲线可视化肿瘤发生率和肿瘤形成时间,并使用广义Wilcoxon检验进行分析。结果:在MMTV-erbB2小鼠中,依维莫司降低了肿瘤发生率,并将中位生存时间从240天增加到410天。在第365天,当对照组小鼠全部死亡时,依维莫司治疗的小鼠中只有一半发生肿瘤(p=0.0001)。依维莫司还能降低p53阴性乳腺小鼠的肿瘤发生率。在420天,50%的对照组小鼠出现乳腺肿瘤,而依维莫司组小鼠只有7%出现乳腺肿瘤(p=0.04)。依维莫司还能降低BRCA1小鼠的肿瘤发生率。262天,对照组18只小鼠中有13只(72%)出现乳腺肿瘤,而依维莫司治疗组18只小鼠中只有7只(38%)出现肿瘤(p=0.02)。依维莫司的长期治疗(>150天)与轻度毒性相关,包括轻微的体重减轻(结论:mTOR抑制剂依维莫司在所有三种小鼠模型中都阻止了乳腺肿瘤的发生。我们的研究结果表明依维莫司可能是一种有效的癌症预防药物,进一步研究减少依维莫司单独使用或与其他靶向治疗联合使用是有必要的。今后应考虑依维莫司的临床试验,以预防高危患者的乳腺癌。由NCI预防癌症临床前药物开发项目(HHSN-2612015000-18I (PB))支持。引文格式:Abhijit Mazumdar, Jamal Hill, Yun Zhang, Lakshmi Reddy Bollu, Alejandro Contreras, Michelle Savage, Shizuko Sei, Altaf Mohammed, powell Brown。靶向mTOR/TORC通路预防er阴性和三阴性乳腺癌[摘要]。摘自:2019年美国癌症研究协会年会论文集;2019年3月29日至4月3日;亚特兰大,乔治亚州。费城(PA): AACR;癌症杂志,2019;79(13增刊):5072。
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