Targeting the Pim 1 Protein Kinase to Overcome Resistance to AKT Inhibitors

靶向 Pim 1 蛋白激酶以克服对 AKT 抑制剂的耐药性

基本信息

批准号：
8577635
负责人：
Andrew S Kraft
金额：
$ 31.02万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2013-09-17 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577635
关键词：
AKT inhibition Animal Model Animals Attention Biochemical Cancer Cell Growth Cell Culture Techniques Cell Death Cell Surface Receptors Cells Clinic Clinical Combined Modality Therapy Complex Data Deletion Mutation Development Disease Disseminated Malignant Neoplasm Dose Drug Targeting Drug resistance Effectiveness Enzymes Feedback Fibroblasts Future Genetic Engineering Genetically Engineered Mouse Gleason Grade for Prostate Cancer Growth Internal Ribosome Entry Site Investigation Laboratories Lead Lentivirus Vector Luciferases Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mediating Metabolic Pathway Metastatic Prostate Cancer Mus Mutation Neoplasm Metastasis Outcome PC3 cell line PIK3CA gene PTEN gene Pathway interactions Patients Pharmaceutical Preparations Play Printing Process Production Prostate Cancer therapy Prostatic Neoplasms Protein Isoforms Protein Kinase Protein Tyrosine Kinase Proto-Oncogene Proteins c-akt Reactive Oxygen Species Receptor Protein-Tyrosine Kinases Regimen Research Research Design Research Personnel Resistance Resistance development Ribosomes Role Secondary to Signal Transduction Pathway Small Interfering RNA Translations United States Work antitumor agent base cancer initiation cell growth design experience foot immunosuppressed inhibitor/antagonist killings kinase inhibitor knock-down leukemia melanoma men mouse model novel novel strategies prostate cancer cell proto-oncogene protein pim public health relevance research study resistance mechanism response small molecule success tissue culture tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): The success of targeting signal transduction pathways for the development of new prostate cancer therapies has been limited to date by the subsequent development of drug resistance mechanisms. Highly activated AKT protein kinase found in almost 70% of cases of metastatic prostate cancer are an important target for therapies in this disease. Preliminary data in this proposal demonstrate that the addition of AKT inhibitors to prostate cancer cell lines induces a marked increase in cell surface receptor tyrosine kinases (RTKs) that function to limit the activity of these inhibitors in part by elevating ERK activity. Importantly, it is also demonstrated that AKT inhibitors induce the Pim-1 protein kinase, an enzyme that has been implicated in prostate cancer initiation and progression. This research team has discovered that knocking down Pim-1 either by siRNA or in genetically engineering mouse fibroblasts will inhibit the feedback in which AKT inhibitors induce RTKs. Using a small molecule Pim-1 inhibitor developed by the Kraft laboratory team, they have demonstrated that the combination of an AKT and Pim-1 inhibitor synergistically blocks prostate cancer cell growth in tissue culture, and markedly inhibits the growth of tumors in immunosuppressed animals. Data obtained suggests that AKT and Pim inhibitors regulate the translation of RTKs. These exciting findings lead to the unique hypothesis that AKT inhibitor treatment causes a Pim-1-directed feedback loop that induces RTKs that in turn stimulates increases in ERK activity. Thus, the combination of an AKT and Pim inhibitor will interrupt the induction of Pim-1 and synergize to kill prostate cancer. The specific aims in this proposal are to explore and validate this hypothesis by: 1) demonstrating in complex cell culture and animal models of prostate cancer that knocking down Pim-1 activity enhances AKT inhibitor tumor killing; 2) deciphering how AKT inhibitors increase the Pim-1 protein kinase and modulate translation to increase RTK levels; and 3) exploring how these agents can be best combined for tumor killing and to inhibit metastatic cancer, and examining whether the combination of AKT and Pim inhibitors induces a marked increase in reactive oxygen species (ROS) in prostate tumors. These studies will identify RTKs, phosphorylated ERK, and Pim-1 levels as potentially clinically important intermediate markers of AKT inhibitor action. The proposed study designs will make use of unique genetically engineered mouse models, and ribosome profiling and foot printing to explore these questions. When completed, these studies will focus attention on the potential for the development of combination therapies with Pim and AKT inhibitors to target feedback resistance mechanisms. This combination would markedly enhance responses to single agent therapies currently under investigation for the treatment of prostate cancer.

描述（由申请人提供）：迄今为止，用于开发新的前列腺癌疗法的靶向信号转导途径的成功受到随后的耐药机制的发展的限制。近 70% 的转移性前列腺癌病例中发现高度活化的 AKT 蛋白激酶，是该疾病治疗的重要靶点。该提案中的初步数据表明，向前列腺癌细胞系中添加 AKT 抑制剂会诱导细胞表面受体酪氨酸激酶 (RTK) 显着增加，RTK 的作用部分是通过提高 ERK 活性来限制这些抑制剂的活性。重要的是，还证明 AKT 抑制剂可诱导 Pim-1 蛋白激酶，这种酶与前列腺癌的发生和进展有关。该研究小组发现，通过 siRNA 或基因工程小鼠成纤维细胞敲低 Pim-1 将抑制 AKT 抑制剂诱导 RTK 的反馈。使用Kraft实验室团队开发的小分子Pim-1抑制剂，他们证明AKT和Pim-1抑制剂的组合可以协同阻断组织培养中前列腺癌细胞的生长，并显着抑制免疫抑制动物的肿瘤生长。获得的数据表明 AKT 和 Pim 抑制剂调节 RTK 的翻译。这些令人兴奋的发现引出了一个独特的假设，即 AKT 抑制剂治疗会导致 Pim-1 导向的反馈回路，从而诱导 RTK，进而刺激 ERK 活性增加。因此，AKT 和 Pim 抑制剂的组合将中断 Pim-1 的诱导并协同杀死前列腺癌。该提案的具体目标是通过以下方式探索和验证这一假设：1）在前列腺癌的复杂细胞培养物和动物模型中证明，敲除 Pim-1 活性可增强 AKT 抑制剂的肿瘤杀伤作用； 2) 破译 AKT 抑制剂如何增加 Pim-1 蛋白激酶并调节翻译以增加 RTK 水平； 3) 探索如何最好地组合这些药物来杀死肿瘤和抑制转移性癌症，并检查 AKT 和 Pim 抑制剂的组合是否会诱导前列腺肿瘤中活性氧 (ROS) 的显着增加。这些研究将确定 RTK、磷酸化 ERK 和 Pim-1 水平作为 AKT 抑制剂作用的潜在临床重要中间标志物。拟议的研究设计将利用独特的基因工程小鼠模型、核糖体分析和足迹来探索这些问题。完成后，这些研究将重点关注开发 Pim 和 AKT 抑制剂联合疗法以靶向反馈抵抗机制的潜力。这种组合将显着增强对目前正在研究的治疗前列腺癌的单药疗法的反应。