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

Akt 抑制剂 MK-2206 用于治疗 PIK3CA 突变和/或 PTEN 缺失的乳腺癌

• 批准号: 8110848
• 负责人: Vandana Abramson
• 金额: $ 29.08万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8110848
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Apoptosis; Autophagocytosis; Biological Markers; Biometry; Blood; Blood Platelets; Breast; Cancer Biology; Cancer Center; Cancer Patient; Cancer Therapy Evaluation Program; Catalytic Domain; Cell Line; Cell Proliferation; Chromosomes, Human, Pair 10; Cleaved cell; Clinical; Clinical Trials; Collaborations; Dana-Farber Cancer Institute; Data; Development; Dose; Dreams; Environment; Focus Groups; Future; Goals; Growth; In Vitro; In complete remission; Laboratory Research; Lead; Malignant Neoplasms; Mediator of activation protein; Metabolism; Molecular; Multicenter Trials; Mutation; Oncogenic; Outcome; PIK3CA gene; PTEN gene; Pathogenesis; Pathway interactions; Patient Selection; Patients; Peripheral Blood Mononuclear Cell; Pharmacodynamics; Phase; Play; Population; Progression-Free Survivals; Proteins; Proteomics; Public Health; Recurrence; Resistance; Signal Transduction; Testing; Therapeutic; Translations; Tumor Suppressor Proteins; Tumor Tissue; Universities; Unresectable; Woman; base; cancer therapy; cancer type; caspase-3; cell growth; cohort; combinatorial; design; efficacy testing; human FRAP1 protein; in vivo; inhibitor/antagonist; innovation; insight; malignant breast neoplasm; molecular oncology; multidisciplinary; mutant; new technology; novel; partial response; pre-clinical; public health relevance; response; response marker; tumor

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.

描述（由申请人提供）：激活的Akt信号传导是乳腺癌发病机制的重要因素。PTEN是PI 3 K/Akt信号传导的负调节因子，在乳腺癌中减少。超过20%的乳腺癌在PIK 3CA中存在突变，PIK 3CA是PI 3 K的p110 α催化亚基，具有Akt依赖性和独立的下游效应。MK 2206是Akt的选择性别构抑制剂。在体外和体内，许多PIK 3CA突变体细胞系和具有PTEN缺失的细胞系对MK 2206敏感。我们假设Akt抑制剂MK2206在患有PIK 3CA突变和/或PTEN缺失的肿瘤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志物和早期药效学变化可以预测临床获益。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，该试验在患有转移性或不可切除的局部晚期或局部复发性乳腺癌的PIK 3CA突变和/或PTEN缺失患者中进行。我们将确定MK2206是否达到客观肿瘤缓解，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结果的基线和药效学标志物。我们将确定MK2206是否抑制Akt信号传导，以及这是否与Ki-67下降、细胞凋亡增加和临床获益相关。我们将确定Akt信号传导的基线激活（通过蛋白质组学和转录特征确定）是否与临床获益相关。我们将确定是否减少Ki-67和/或增加细胞凋亡在2周与效益。我们将比较MK 2206对肿瘤和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信号传导是对一些现有乳腺癌疗法的抗性的介导物。我们将确定MK2206是否在PI 3 KCA突变或PTEN缺失的患者中具有抗肿瘤活性。我们将确定MK2206在临床耐受剂量下是否确实抑制Akt，我们将进行探索性研究以确定反应的预测因子和药效学标志物。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，这些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信号在乳腺癌以及许多其他肿瘤类型中很常见。我们将确定一种新型Akt抑制剂MK2206是否在基于分子亚型选择的晚期乳腺癌患者中具有抗肿瘤活性，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获益。