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：
8735893
负责人：
Andrew S Kraft
金额：
$ 7.23万
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 2014-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8735893
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）：靶向信号转导途径成功开发新的前列腺癌疗法的成功已受到抗药性机制的随后发展而受到限制。在几乎70％的转移性前列腺癌病例中发现的高度激活的Akt蛋白激酶是该疾病疗法的重要靶标。该提案中的初步数据表明，在前列腺癌细胞系中添加AKT抑制剂可引起细胞表面受体酪氨酸激酶（RTKS）的显着增加，从而通过提高ERK活性来限制部分抑制剂的活性。重要的是，还证明AKT抑制剂诱导PIM-1蛋白激酶，这是一种与前列腺癌的启动和进展有关的酶。该研究团队发现，siRNA或在基因工程中击倒PIM-1的小鼠成纤维细胞将抑制AKT抑制剂诱导RTK的反馈。他们使用牛皮纸实验室小组开发的小分子PIM-1抑制剂，证明AKT和PIM-1抑制剂的结合可以协同阻断组织培养的前列腺癌细胞的生长，并显着抑制免疫抑制动物中肿瘤的生长。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导致了一个独特的假设，即Akt抑制剂治疗引起了PIM-1指导的反馈回路，该反馈循环诱导RTK，进而刺激ERK活性的增加。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。该提案中的具体目的是通过以下方式探索和验证这一假设：1）在复杂的细胞培养和前列腺癌的动物模型中证明，击倒PIM-1活性增强了Akt抑制剂肿瘤的杀戮； 2）解密AKT抑制剂如何增加PIM-1蛋白激酶并调节翻译以提高RTK水平； 3）探索这些药物如何最好地结合肿瘤杀伤和抑制转移性癌，并检查Akt和PIM抑制剂的组合是否会诱导前列腺肿瘤中的活性氧（ROS）显着增加。这些研究将鉴定RTK，磷酸化的ERK和PIM-1水平是AKT抑制剂作用的潜在临床上重要的中间标记。拟议的研究设计将利用独特的基因工程鼠标模型以及核糖体分析和脚印来探索这些问题。完成后，这些研究将重点关注与PIM和AKT抑制剂开发组合疗法的潜力，以靶向反馈抗性机制。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一药物疗法的反应。