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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：
7535139
负责人：
Jin Q Cheng
金额：
$ 32.18万
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 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7535139
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（申请人提供）：AKT是诱导细胞存活、生长和转化的主要途径。从AKT家族中鉴定出AKT1、AKT2和AKT3三个亚型。AKT的频繁改变，尤其是AKT2，已经在人类恶性肿瘤中被检测到。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细胞凋亡敏感。通过筛选来自14万种化合物的NCI多样性集，我们最近获得了30多种化合物，它们在akt2转化的NIH 3T3细胞中显著抑制生长，而在pcdna3转染的NIH 3T3细胞中则没有。进一步分析表明，其中两种直接抑制AKT2激酶活性，另外两种直接降低AKT磷酸化。所有四种化合物都能显著抑制AKT通路改变的三种人类癌细胞系的生长。基于这些发现，我们假设AKT是癌症干预的关键治疗靶点，AKT信号的特异性抑制剂会降低AKT活性升高的肿瘤的致瘤性。由于抑制AKT可诱导多种哺乳动物细胞凋亡，因此AKT抑制剂与其他抗癌药物联合治疗具有其他基因改变的肿瘤可能是有效的。由于积累的研究清楚地显示了AKT的三种亚型之间的生物学/生理功能差异，鉴定每种亚型的抑制剂将提高治疗效果并减少副作用。这项研究的基本原理是AKT在人类恶性肿瘤中经常发生改变，抑制AKT可诱导细胞凋亡和细胞生长停滞。因此，开发特异性AKT抑制剂在改善癌症治疗方面具有很大的潜力，并为表征AKT信号转导途径提供了额外的手段。该项目的目的是开发特异性的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)验证AKT1， AKT2和AKT3作为人类癌症的治疗靶点，并通过高通量筛选合成AKT底物模拟物和NCI多样性集的化合物，确定先导化合物作为AKT的潜在干扰物。(2)确定先导化合物抑制AKT通路的特异性。(3)研究有希望的AKT抑制剂在完整细胞中破坏AKT信号通路的能力，并通过野生型和组成型活性AKT 1、AKT2和AKT3抑制细胞转化。(4)在PI3K/PTEN/AKT通路改变的人类肿瘤细胞培养和动物模型中评估活性化合物的抗肿瘤效果。