Novel regulation of PI3K/Akt to direct targeted breast cancer therapies

PI3K/Akt 的新调控可指导乳腺癌靶向治疗

基本信息

批准号：
8559337
负责人：
Alex Toker
金额：
$ 36.11万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-16 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8559337
关键词：
Address Adverse effects Advocate Animal Model Antineoplastic Agents Apoptosis Automobile Driving Biochemical Breast Breast Cancer Cell Cancer Cell Growth Cancer Patient Cell Culture Techniques Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Survival Cell division Cell physiology Clinic Clinical Trials Collaborations Combined Modality Therapy Complex Coupled Cullin 1 Cyclin A Data Development Engineering Epithelial Cells Event Exhibits F Box Domain Genes Goals Growth Growth Factor Human In Vitro Individual Joints Laboratories Lead Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Modeling Molecular Mutation Nature Normal Cell Oncogenic PIK3CA gene PTEN gene Pathway interactions Patients Phase I/II Trial Phenocopy Phenotype Phosphatidylinositols Phosphotransferases Regulation Regulatory Pathway Research Personnel Role Signal Pathway Signal Transduction Somatic Cell Somatic Mutation Testing Therapeutic Toxic effect Transgenic Mice Treatment Efficacy Tumor Suppression Ubiquitination Work Xenograft procedure base cancer cell cancer therapy cell growth combat design in vivo in vivo Model inhibitor/antagonist insight insulin signaling interest killings malignant breast neoplasm mouse model new therapeutic target novel novel therapeutic intervention overexpression prevent public health relevance research study response small molecule triple-negative invasive breast carcinoma tumor tumor growth tumorigenesis ubiquitin-protein ligase

Address Adverse effects Advocate Animal Model Antineoplastic Agents Apoptosis Automobile Driving Biochemical Breast Breast Cancer Cell Cancer Cell Growth Cancer Patient Cell Culture Techniques Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Survival Cell division Cell physiology Clinic Clinical Trials Collaborations Combined Modality Therapy Complex Coupled Cullin 1 Cyclin A Data Development Engineering Epithelial Cells Event Exhibits F Box Domain Genes Goals Growth Growth Factor Human In Vitro Individual Joints Laboratories Lead Malignant Neoplasms Mammary Neoplasms Mammary gland Mediating Modeling Molecular Mutation Nature Normal Cell Oncogenic PIK3CA gene PTEN gene Pathway interactions Patients Phase I/II Trial Phenocopy Phenotype Phosphatidylinositols Phosphotransferases Regulation Regulatory Pathway Research Personnel Role Signal Pathway Signal Transduction Somatic Cell Somatic Mutation Testing Therapeutic Toxic effect Transgenic Mice Treatment Efficacy Tumor Suppression Ubiquitination Work Xenograft procedure base cancer cell cancer therapy cell growth combat design in vivo in vivo Model inhibitor/antagonist insight insulin signaling interest killings malignant breast neoplasm mouse model new therapeutic target novel novel therapeutic intervention overexpression prevent public health relevance research study response small molecule triple-negative invasive breast carcinoma tumor tumor growth tumorigenesis ubiquitin-protein ligase

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项目摘要

DESCRIPTION (provided by applicant): The PI 3-K/Akt signaling axis is critical for both the initiation and progression of many cancers, including breast cancer, by promoting cancer cell survival and growth. Akt hyperactivation is observed in a large proportion of patients and is considered a hallmark of cancer. Much is known concerning the mechanisms that govern PI 3- K activation, and in turn Akt regulation and signaling to phenotypes associated with malignancy. This molecular information has enabled the development of PI 3-K and Akt inhibitors for cancer therapy, and many of these are in phase I and II trials. However, small molecule Akt inhibitors have shown side effects with toxicity in normal somatic cells, reflecting the fact that Akt is essential for various normal cellular functions. In contrast, uncontrolled cell division is another hallmark of human cancer, whereas most normal somatic cells are in a non-dividing, quiescent state. Consequently, certain cell cycle regulators such as Cyclin A, frequently overexpressed in cancer, are considered promising anti-cancer targets. To date, an intrinsic connection between Akt hyperactivation and aberrant cell cycle regulation has not been defined. Our preliminary studies show that Akt activity fluctuates during cell cycle and mirrors Cyclin A expression. Moreover, depletion of Cyclin A or Cdk2 dramatically reduces Akt activity, suggesting that Cdk2/Cyclin A inhibitors may specifically kill breast cancer cells with no effect of normal somatic cells. In Aim 1, we propose that aberrant activation of Cdk2/Cyclin A in breast cancer contributes to hyperactivation of Akt. We will mechanistically define how Cdk2/Cyclin A functions as a novel upstream regulatory mechanism to promote Akt activation in a cell cycle- dependent manner. We will determine whether Cdk2 inhibitors can suppress breast cancer cell growth in vitro and in vivo. In Aim 2, we show preliminary evidence that in a subset of triple-negative breast cancer cells, reactivation of Akt occurs subsequent to PI 3-K inhibition, and in a manner dependent on the E3 ubiquitin ligase Skp2. We will investigate the mechanistic basis for Skp2-mediated reactivation of Akt to drive phenotypes associated with malignancy in breast cancer cells. Furthermore, somatic mutations in Akt1 and Akt2 at E17K have been identified in breast cancer patients. In our preliminary studies, we show that Akt2 E17K can promote signaling and proliferation of breast epithelial cells in a growth factor and PI 3-K- independent manner, whereas Akt1 E17K cannot. We will explore the mechanistic basis for this distinction in vitro and using transgenic mice expressing Akt1 and Akt2 E17K, and examine the contribution of Skp2 in this event. Our goal in Aim 2 is to define the precise mechanisms that govern Akt activation in a PI 3-K- independent manner in breast cancer. Overall, we believe that our proposed studies will provide new molecular insights into the activation of Akt in breast tumors, that would be unresponsive to PI 3-K inhibitors. Instead, our studies will inform the use of Cdk2, Skp2 and Akt inhibitors for targeted therapy to achieve optimal treatment efficacy in the clinic.

描述（由申请人提供）：PI 3-K/AKT信号轴对于通过促进癌细胞的存活和生长来促进许多癌症（包括乳腺癌）的起始和进展至关重要。在很大一部分患者中观察到AKT过度激活，被认为是癌症的标志。关于控制PI 3- K激活的机制以及对与恶性肿瘤相关的表型的信号传导的机制，众所周知。该分子信息使PI 3-K和AKT抑制剂用于癌症治疗，其中许多是在I期和II期试验中。然而，小分子AKT抑制剂显示出正常体细胞中毒性的副作用，这反映了AKT对于各种正常细胞功能至关重要的事实。相反，不受控制的细胞分裂是另一个人类癌症的标志，而大多数正常的体细胞处于非分裂的静态状态。因此，某些细胞周期调节剂（例如细胞周期蛋白A）在癌症中经常过表达，被认为是有希望的抗癌靶标。迄今为止，尚未定义AKT过度激活与异常细胞周期调节之间的固有联系。我们的初步研究表明，AKT活性在细胞周期中波动，并反映了细胞周期蛋白A表达。此外，细胞周期蛋白A或CDK2的耗竭大大降低了AKT活性，表明CDK2/细胞周期蛋白A抑制剂可能会特别杀死乳腺癌细胞而没有正常体细胞的影响细胞。在AIM 1中，我们提出，乳腺癌中CDK2/细胞周期蛋白A的异常激活会导致AKT过度激活。我们将从机械上定义CDK2/Cyclin A作为一种新型上游调节机制如何以细胞周期依赖性方式促进Akt激活。我们将确定CDK2抑制剂是否可以在体外和体内抑制乳腺癌细胞的生长。在AIM 2中，我们显示了初步证据，表明在三阴性乳腺癌细胞的子集中，Akt的重新激活发生在PI 3-K抑制后，并且以E3泛素连接酶SKP2的方式发生。我们将研究SKP2介导的AKT重新激活的机理基础，以驱动与乳腺癌细胞中恶性肿瘤相关的表型。此外，在乳腺癌患者中已经确定了E17K Akt1和Akt2中的体细胞突变。在我们的初步研究中，我们表明AKT2 E17K可以以生长因子和PI 3-K-独立方式促进乳腺上皮细胞的信号传导和增殖，而AKT1 E17K不能。我们将探讨这种在体外区分的机理基础，并使用表达AKT1和AKT2 E17K的转基因小鼠，并在此事件中检查SKP2的贡献。我们的目标2的目标是定义以PI 3-K-独立方式在乳腺癌中使用AKT激活的精确机制。总体而言，我们认为我们的拟议研究将为乳腺肿瘤中AKT的激活提供新的分子见解，这对PI 3-K抑制剂无反应。取而代之的是，我们的研究将为CDK2，SKP2和AKT抑制剂用于靶向疗法的使用，以在临床中实现最佳治疗疗效。