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

描述(申请人提供)：该项目的目标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动态平衡的转变和增强的合成代谢，以实现快速生长和持续增殖。真核细胞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是由AMP/ATP比率的变化触发的，从而影响能量储备和需求。AMPK通路与PI3K/AKT信号通路密切相互作用，影响主调控因子mTOR的下游功能。在细胞系中，二甲双胍(即AMPK激活剂)和单独使用他汀类药物(即HMG CoA还原酶抑制剂)的双重治疗已显示出协同作用，预计联合治疗可能比单一药物治疗具有更大的抗癌效果。使用单剂二甲双胍的手术前“机会之窗”研究结果喜忧参半，而使用他汀类药物的手术前研究报告了早期可手术乳腺癌患者的增殖减少和细胞凋亡增加。利用手术前模型，我们计划对40名新诊断为浸润性乳腺癌的女性进行一项试点研究，在诊断性乳房活检和最终乳房手术之间的间隔时间内，每天服用二甲双胍和阿托伐他汀至少两周。在这项手术前试验中，患者将在每天的睡前服用二甲双胍(1500毫克，早晚各500毫克和1000毫克)和阿托伐他汀80毫克。具体目标1是评估在新诊断的乳腺癌患者手术前联合应用二甲双胍和阿托伐他汀至少2周是否会改变肿瘤的增殖，这是通过降低乳腺肿瘤细胞Ki-67的自然对数表达来衡量的。具体目的#2是评估AMPK/mTOR和胰岛素生长因子信号通路的变化，以及通过反相蛋白芯片(RPPA)和基于血液的生物标志物在细胞凋亡中的变化。这项试验的结果将直接与我们机构最近完成的单剂二甲双胍的手术前试验进行比较，作为对照。我们假设二甲双胍联合他汀类药物治疗将有更大程度的抑制细胞增殖，表现为Ki-67的表达。。我们还预计AMPK/mTOR通路的调节、细胞凋亡的增加和IGF通路标志物的减少。这项手术前试验的结果将有助于将来利用二甲双胍和他汀类药物治疗乳腺癌妇女的临床试验的发展。

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.