Pre-Surgical trial of Metformin and Atorvastatin in Operable Breast Cancer

描述（由申请方提供）：本项目的目的是确定二甲双胍联合阿托伐他汀在可手术乳腺癌患者中是否具有显著的抗增殖活性。乳腺癌细胞需要能量稳态的转变，增强免疫力，以实现快速生长和持续增殖。在真核生物和乳腺癌细胞中的主要能量调节系统是AMP激活的激酶（AMPK）途径。AMPK由AMP/ATP比率的变化触发，从而影响能量储备和需求。AMPK通路与PI 3 K/AKT信号通路密切相互作用，影响主调节因子mTOR的下游功能。在细胞系中，二甲双胍（即AMPK激活剂）和他汀类药物（即HMG CoA还原酶抑制剂）的双重治疗已显示出协同活性，预计联合治疗可能比单药治疗具有更大的抗癌作用。二甲双胍单药的术前“机会窗口”研究显示了混合的结果，而他汀类药物的术前研究报告了早期可手术乳腺癌女性的增殖减少和凋亡增加。利用术前模型，我们计划对40名新诊断的浸润性乳腺癌女性进行一项试点研究，在诊断性乳腺活检和确定性乳腺手术之间，每天口服二甲双胍和阿托伐他汀至少两周。在这项术前试验中，患者将在睡前接受二甲双胍（1500 mg/天：分为早晨500 mg和晚上1000 mg）和阿托伐他汀80 mg/天一次。具体目标#1是评估在新诊断的乳腺癌患者中，二甲双胍和阿托伐他汀联合治疗至少2周是否会改变肿瘤增殖，如通过乳腺肿瘤细胞ki-67的自然对数表达的降低所测量的。具体目标#2是通过反相蛋白微阵列（RPPA）以及基于血液的生物标志物来评估AMPK/mTOR和胰岛素生长因子通路信号传导和细胞凋亡的变化。本试验的结果将直接与我们机构最近完成的二甲双胍单药术前试验（作为对照）进行比较。我们假设二甲双胍联合他汀类药物治疗可更大程度地降低细胞增殖，如ki-67表达所示。.我们还预期AMPK/mTOR通路的调节、凋亡的增加和IGF通路标志物的减少。这项术前试验的结果将有助于未来利用二甲双胍和他汀类药物治疗乳腺癌女性的临床试验的发展。

DESCRIPTION (provided by applicant): The goal of this project is to determine whether the combination of metformin plus atorvastatin has significant anti-proliferative activity in patients with operable breast cancer. Breast cancer cells require energy homeostasis shifts with enhanced anabolism to enable rapid growth and continued proliferation. The main energy regulatory system in eukaryotes and breast cancer cells is the AMP-activated kinase (AMPK) pathway. AMPK is triggered by changes in the AMP/ATP ratio, thus impacting energy reserves and requirements. AMPK pathway closely interacts with the PI3K/AKT signaling pathway, affecting downstream function of the master regulator mTOR. In cell lines, dual therapy with both metformin (i.e. an AMPK activator) and with statins alone (i.e. HMG CoA reductase inhibitors) has demonstrated synergistic activity, with the anticipation that combination therapy may have a greater anti-cancer impact than single agent treatments. Pre-surgical "window of opportunity" studies with single agent metformin have demonstrated mixed results, while pre-surgical studies with statins reporting a reduction of proliferation and increase in apoptosis in women with early stage operable breast cancer. Utilizing a pre-surgical model, we plan to conduct a pilot study of 40 women with newly diagnosed invasive breast cancer will receive oral metformin and atorvastatin daily for at least two weeks, in the interval between diagnostic breast biopsy and definitive breast surgery. In this pre-surgical trial, patients will receive metformin (1500mg per day: divided 500mg in the morning and 1000mg in the evening) and atorvastatin 80mg once a day at bedtime. Specific Aim #1 is to assess whether pre-surgical treatment with the combination metformin and atorvastatin for at least 2 weeks will alter tumor proliferation, as measured by decrease in the natural log expression of ki-67 of breast tumor cells, in patients with newly diagnosed breast cancer. Specific Aim #2 is to evaluate changes in AMPK/mTOR and insulin growth factor pathways signaling and in apoptosis by reverse phase protein microarray (RPPA) as well as in blood-based biomarkers. The results of this trial will be directly compared to a recently completed pre- surgical trial of single-agent metformin at our institution, serving as a control. We hypothesize that treatment with metformin in combination with a statin will have a greater reduction in cellular proliferation as manifested by ki-67 expression. . We also anticipate modulation of the AMPK/mTOR pathway, increase in apoptosis, and reduction in IGF pathway markers. Results from this pre-surgical trial will aid in the development of future clinical trials utilizing metformin and statin in the treatment of women with breast cancer.