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信号是乳腺癌发病机制的重要因素。PTEN是PI3K/Akt信号的负调控因子，在乳腺癌中表达降低。超过20%的乳腺癌存在PIK3CA突变，PIK3CA是PI3K的p110α催化亚单位，具有Akt依赖和独立的下游效应。MK2206是Akt的选择性变构抑制剂。在体内外，许多突变的PIK3CA细胞系和PTEN缺失的细胞系对MK2206敏感。我们假设Akt抑制剂MK2206对具有PIK3CA突变和/或PTEN缺失的晚期乳腺癌患者具有抗肿瘤活性，并且肿瘤和血液中的基线标志物和早期药效学变化可以预测临床益处。在目标1中，我们将在CTEP批准的II期多中心试验中确定MK2206是否具有抗肿瘤活性，这些试验适用于具有PIK3CA突变和/或PTEN缺失的转移性、局部晚期或局部复发乳腺癌患者。我们将确定MK2206是否达到了客观的肿瘤反应，并确定了6个月的无进展生存期。我们将在治疗两周后确定MK2206是否会抑制细胞增殖和/或增加细胞凋亡。在目标2中，我们将确定可能预测结果的肿瘤组织和血液中的基线和药效学标记物。我们将确定MK2206是否抑制Akt信号转导，以及这是否与Ki-67的下降、细胞凋亡的增加和临床益处相关。我们将确定Akt信号的基线激活(由蛋白质组和转录特征确定)是否与临床益处相关。我们将确定2周时Ki-67的减少和/或细胞凋亡的增加是否与收益相关。我们将比较MK2206对肿瘤以及外周血单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。激活的Akt信号是一些现有乳腺癌治疗方法耐药的介体。我们将确定MK2206在PI3KCA突变或PTEN缺失的患者中是否具有抗肿瘤活性。我们将确定MK2206是否确实在临床耐受剂量下抑制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患者最有可能受益于MK2206。由于Akt在许多癌症中都被激活，因此结果将对其他几种癌症类型的患者产生影响。 公共卫生相关性：乳腺癌是一个主要的公共卫生问题。AKT信号在乳腺癌和许多其他类型的肿瘤中很常见。我们将根据分子亚型确定新型Akt抑制剂MK2206在选择的晚期乳腺癌患者中是否具有抗肿瘤活性，以及MK2206在肿瘤和血液中诱导的基线标志物和早期变化是否可以预测临床益处。

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. PUBLIC HEALTH RELEVANCE: Breast cancer is a major public health problem. Akt signaling is common in breast cancer as well as in many other tumor types. We will determine whether a novel Akt inhibitor MK2206 has antitumor activity in advanced breast cancer patients selected based on molecular subtype, and whether baseline markers and early changes induced by MK2206 in the tumor and blood can predict clinical benefit.