Akt Inhibitor MK-2206 for Breast Cancers with a PIK3CA Mutation and/or PTEN loss

描述（由申请人提供）：激活的Akt信号是乳腺癌发病的重要因素。PTEN是PI3K/Akt信号的负调控因子，在乳腺癌中表达减少。超过20%的乳腺癌存在PIK3CA突变，PI3K的p110 α催化亚基，具有akt依赖性和独立的下游作用。MK2206是Akt的选择性变构抑制剂。在体外和体内实验中，许多PIK3CA突变细胞系和PTEN缺失细胞系对MK2206敏感。我们假设Akt抑制剂MK2206在PIK3CA突变和/或PTEN缺失的晚期乳腺癌患者中具有抗肿瘤活性，并且肿瘤和血液中的基线标记物和早期药理学变化可以预测临床获益。在目标1中，我们将在一项ctep批准的II期多中心试验中确定MK2206是否具有抗肿瘤活性，该试验适用于PIK3CA突变和/或PTEN缺失的转移性、不可切除的局部晚期或局部复发乳腺癌患者。我们将确定MK2206是否达到客观肿瘤反应，并确定6个月无进展生存期。我们将在治疗两周后确定MK2206是否会降低细胞增殖和/或增加细胞凋亡。在目标2中，我们将确定肿瘤组织和血液中可能预测预后的基线和药效学标志物。我们将确定MK2206是否抑制Akt信号，以及这是否与Ki-67的下降、细胞凋亡的增加和临床获益相关。我们将确定Akt信号的基线激活（由蛋白质组学和转录特征决定）是否与临床获益相关。我们将确定在2周时Ki-67的降低和/或细胞凋亡的增加是否与获益相关。我们将比较MK2206对肿瘤和外周血单个核细胞和血小板的影响。公共卫生相关性：乳腺癌是一个主要的公共卫生问题。活化的Akt信号是对一些现有乳腺癌治疗的耐药的中介。我们将确定MK2206是否对PI3KCA突变或PTEN缺失的患者具有抗肿瘤活性。我们将确定MK2206是否在临床耐受剂量下确实抑制Akt，我们将进行探索性研究，以确定反应的预测因素和药效学标志物。这些研究将阐明哪些乳腺癌人群最有可能从MK2206中获益。由于Akt在许多癌症中被激活，该研究结果将对其他几种癌症患者产生影响。

DESCRIPTION (provided by applicant): Activated Akt signaling is a significant contributor to the pathogenesis of breast cancer. PTEN is a negative regulator of PI3K/Akt signaling and is decreased in breast cancer. Over 20% of breast cancers have mutations in PIK3CA, the p110alpha catalytic subunit of PI3K, with Akt-dependent and independent downstream effects. MK2206 is a selective allosteric inhibitor of Akt. In vitro and in vivo, many of the PIK3CA mutant cell lines and cell lines with PTEN loss are sensitive to MK2206. We hypothesize that Akt inhibitor MK2206 has antitumor activity in advanced breast cancer patients who have tumors with a PIK3CA mutation and/or PTEN loss, and that baseline markers and early pharmacodynamic changes in tumor and blood can predict clinical benefit. In aim 1, we will determine whether MK2206 has anti-tumor activity in a CTEP-approved Phase II multicenter trial in patients with metastatic, or unresectable locally advanced, or locally recurrent breast cancer with PIK3CA mutations and/or PTEN loss. We will determine whether MK2206 achieves objective tumor responses and determine the 6 month progression-free survival. We will determine whether MK2206 decreases cell proliferation and/or increases apoptosis after two weeks of treatment. In Aim 2, we will determine baseline and pharmacodynamic markers in tumor tissue and blood that may predict outcome. We will determine whether MK2206 inhibits Akt signaling, and if this correlates with a decline in Ki-67, increase in apoptosis, and clinical benefit. We will determine whether baseline activation of Akt signaling (as determined by proteomic and transcriptional signatures) correlate with clinical benefit. We will determine whether decrease in Ki-67 and/or increase in apoptosis at 2 weeks correlate with benefit. We will compare the effect of MK2206 on the tumor and in peripheral blood mononuclear cells and platelets. Public Health Relevance: Breast cancer is a major public health problem. Activated Akt signaling is mediator of resistance to some of the existing breast cancer therapies. We will determine whether MK2206 has antitumor activity in patients with PI3KCA mutations or PTEN loss. We will determine whether MK2206 indeed inhibits Akt in clinically tolerated doses, and we will perform exploratory studies to identify predictors and pharmacodynamic markers of response. These studies will elucidate which breast cancer populations are most likely to benefit from MK2206. As Akt is activated in many cancers, are results will have implications for patients with several other cancer types.