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Disruption of AKT Pathway for Cancer Intervention

破坏 AKT 通路以干预癌症

基本信息

批准号：
7426857
负责人：
Jin Q Cheng
金额：
$ 38.29万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7426857
关键词：
AKT inhibition AKT1 gene AKT2 gene AKT3 gene Adverse effects Affinity Animal Model Antineoplastic Agents Apoptosis Binding Biological Biological Assay Breast Cancer Cell Growth Cancer Intervention Cancer cell line Cell Death Cell Proliferation Cell Survival Cells Cisplatin Complex Consensus Sequence Cultured Cells Cyclic AMP-Dependent Protein Kinases Development Disruption Dominant-Negative Mutation Ectopic Expression Facility Construction Funding Category Family Gene Mutation Goals Growth Human ILK gene Inhibition of Apoptosis Lead MAP3K5 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Mammalian Cell Modeling NIH 3T3 Cells Neoplasm Metastasis Normal Cell Ovarian PDPK1 gene PI3K/AKT Paclitaxel Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Physiological Protein Isoforms Protein Overexpression Proto-Oncogene Proteins c-akt RNA Interference Range Research Resistance Screening procedure Signal Transduction Signal Transduction Pathway Site Specificity Structure TSC2 gene Toxic effect Treatment Efficacy Tumor Suppressor Proteins Tumorigenicity base cancer cell cancer therapy cell growth cell transformation chemical synthesis chemotherapeutic agent compound 30 design experience farnesyltranstransferase high throughput screening improved inhibitor/antagonist integrin-linked kinase member mimetics novel peptidomimetics protein aminoacid sequence protein farnesyltransferase protein geranylgeranyltransferase rac-PK beta research study therapeutic target tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): AKT is a major pathway to induce cell survival, growth and transformation. Three isoforms, AKT1, AKT2 and AKT3, have been identified from the AKT family. Frequent alterations of AKT, especially AKT2, have been detected in human malignancies. Ectopic expression of AKT induces chemo-resistance, whereas, dominant negative AKT sensitizes cells to chemotherapeutic drug-induced apoptosis. By screening the NCI diversity set that was derived from 140,000 compounds, we have recently obtained more than 30 compounds that significantly inhibited growth in AKT2-transformed, but not in pcDNA3-transfected NIH 3T3 cells. Further analyses show that two of them directly inhibited constitutively active AKT2 kinase activity, and another two directly decreased AKT phosphorylation. All four (4) compounds significantly inhibit growth in three (3) human cancer cell lines where the AKT pathway is altered. Based on these findings, we hypothesize that AKT is a critical therapeutic target for cancer intervention and that specific inhibitor(s) of AKT signaling will reduce tumorigenicity in tumors with elevated AKT activity. Since inhibition of AKT induces apoptosis in a range of mammalian cells, AKT inhibitor(s) could be effective, in combination with other anticancer drugs, for the treatment of tumors with other gene alterations. As accumulated studies show clearly biological/physiological function differences between three (3) isoforms of AKT, identification of inhibitor(s) for each isoform of AKT will enhance therapeutic efficacy and reduce side effects. The rationale for the proposed research is that AKT is frequently altered in human malignancy and that inhibition of AKT induces apoptosis and cell growth arrest. Therefore, development of specific AKT inhibitor(s) has great potential to improve cancer treatment and provide additional means to characterize the AKT signal transduction pathway. The objective of this project is to develop specific AKT inhibitors and evaluate their abilities to reverse malignant transformation of human tumors by disruption of the AKT pathway without gross toxicity. The specific aims are: (1) Validate AKT1, AKT2, and AKT3 as therapeutic targets in human cancer and identify lead compounds as potential disruptors of AKT by high-throughput screening of compounds from synthetic AKT substrate mimics and the NCI diversity set. (2) Determine the specificity of lead compounds in the inhibition of AKT pathway. (3) Examine the abilities of promising AKT inhibitor(s) to disrupt AKT signaling in intact cells and inhibit cell transformation by wild type and constitutively active AKT 1, AKT2 and AKT3. (4) Evaluate anti-tumor efficacy of active compounds in cell culture and animal models of human cancers where the PI3K/PTEN/AKT pathway is altered.

描述（由申请人提供）：AKT是诱导细胞存活、生长和转化的主要途径。AKT家族有三种亚型，AKT 1、AKT 2和AKT 3。在人类恶性肿瘤中已检测到AKT，尤其是AKT 2的频繁改变。AKT的异位表达诱导化疗耐药，而显性阴性AKT使细胞对化疗药物诱导的凋亡敏感。通过筛选来自140，000种化合物的NCI多样性集，我们最近获得了超过30种化合物，它们显著抑制AKT 2转化的NIH 3 T3细胞的生长，但不抑制pcDNA 3转染的NIH 3 T3细胞的生长。进一步的分析表明，其中两种直接抑制组成型活性AKT 2激酶活性，另外两种直接降低AKT磷酸化。所有四（4）种化合物均显著抑制其中AKT途径改变的三（3）种人癌细胞系的生长。基于这些发现，我们假设AKT是癌症干预的关键治疗靶点，并且AKT信号传导的特异性抑制剂将降低AKT活性升高的肿瘤的致瘤性。由于AKT的抑制在一系列哺乳动物细胞中诱导细胞凋亡，因此AKT抑制剂与其他抗癌药物组合可有效治疗具有其他基因改变的肿瘤。由于累积的研究清楚地显示AKT的三种（3）亚型之间的生物学/生理学功能差异，因此鉴定AKT的每种亚型的抑制剂将增强治疗功效并减少副作用。这项研究的基本原理是，AKT在人类恶性肿瘤中经常发生变化，抑制AKT会诱导细胞凋亡和细胞生长停滞。因此，开发特异性AKT抑制剂具有改善癌症治疗的巨大潜力，并提供表征AKT信号转导途径的额外手段。本项目的目的是开发特异性AKT抑制剂，并评估其通过破坏AKT通路而无明显毒性逆转人类肿瘤恶性转化的能力。具体目标是：（1）通过从合成AKT底物模拟物和NCI多样性集合中高通量筛选化合物，将AKT 1、AKT 2和AKT 3作为人类癌症的治疗靶标，并将先导化合物鉴定为AKT的潜在干扰物。(2)确定先导化合物抑制AKT途径的特异性。(3)检查有希望的AKT抑制剂在完整细胞中破坏AKT信号传导并抑制野生型和组成型活性AKT 1、AKT 2和AKT 3的细胞转化的能力。(4)评估活性化合物在PI 3 K/PTEN/AKT通路改变的人类癌症的细胞培养物和动物模型中的抗肿瘤功效。