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

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 信号传导轴通过促进癌细胞存活和生长，对于包括乳腺癌在内的许多癌症的发生和进展至关重要。在大部分患者中观察到 Akt 过度激活，这被认为是癌症的标志。关于控制 PI 3-K 激活的机制以及 Akt 调节和与恶性肿瘤相关表型的信号转导，人们已经了解很多。这些分子信息使得用于癌症治疗的 PI 3-K 和 Akt 抑制剂的开发成为可能，其中许多处于 I 期和 II 期试验中。然而，小分子 Akt 抑制剂在正常体细胞中表现出毒性副作用，反映出 Akt 对于各种正常细胞功能至关重要。相反，不受控制的细胞分裂是另一种情况这是人类癌症的标志，而大多数正常体细胞处于不分裂的静止状态。因此，某些细胞周期调节因子（例如细胞周期蛋白 A）在癌症中经常过度表达，被认为是有希望的抗癌靶点。迄今为止，Akt 过度激活与异常细胞周期调节之间的内在联系尚未明确。我们的初步研究表明 Akt 活性在细胞周期中波动并反映了 Cyclin A 的表达。此外，Cyclin A 或 Cdk2 的耗竭会显着降低 Akt 活性，这表明 Cdk2/Cyclin A 抑制剂可以特异性杀死乳腺癌细胞，而不会影响正常体细胞细胞。在目标 1 中，我们提出乳腺癌中 Cdk2/Cyclin A 的异常激活导致 Akt 过度激活。我们将机械地定义 Cdk2/Cyclin A 如何作为一种新型上游调节机制发挥作用，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。在目标 2 中，我们展示了初步证据，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 抑制之后，并且以依赖于 E3 泛素连接酶 Skp2 的方式重新激活。我们将研究 Skp2 介导的 Akt 重新激活以驱动与乳腺癌细胞恶性肿瘤相关的表型的机制基础。此外，在乳腺癌患者中还发现了 Akt1 和 Akt2 E17K 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 独立的方式促进乳腺上皮细胞的信号传导和增殖，而 Akt1 E17K 则不能。我们将在体外并使用表达 Akt1 和 Akt2 E17K 的转基因小鼠探索这种区别的机制基础，并检查 Skp2 在此事件中的贡献。我们的目标 2 是确定乳腺癌中以 PI 3-K 独立方式控制 Akt 激活的精确机制。总的来说，我们相信我们提出的研究将为乳腺肿瘤中 Akt 的激活提供新的分子见解，而乳腺肿瘤对 PI 3-K 抑制剂没有反应。相反，我们的研究将告知使用Cdk2、Skp2和Akt抑制剂进行靶向治疗，以在临床上达到最佳治疗效果。