Elucidating a Novel Akt Activation Mechanism for Targeted Prostate Cancer Therapy

阐明前列腺癌靶向治疗的新型 Akt 激活机制

基本信息

批准号：
9231531
负责人：
Pengda Liu
金额：
$ 21.75万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231531
关键词：
1-Phosphatidylinositol 3-Kinase Abnormal Cell Agar American Animals Antibodies Antineoplastic Agents Apoptotic Attenuated Award Basic Science Binding Sites Biological Assay CCNE1 gene Cancer Patient Cell Culture System Cell Cycle Cells Chemicals Clinical Trials Complex Cyclin A DNA Damage Data Development Dissection Drug Targeting Etoposide Event Future Goals Growth Health Hormones Human In Vitro Induction of Apoptosis Intervention Israel Left Life Malignant Neoplasms Malignant neoplasm of prostate Mediating Medical center Methods Molecular Molecular and Cellular Biology Mus Mutate Neoplasm Metastasis Normal Cell Oncogenes Oncogenic Outcome Pathway interactions Pattern Phase Phenotype Phosphorylation Phosphotransferases Physiological Play Problem Solving Process Prostate Prostate Cancer therapy Prostatic Neoplasms Protein Kinase Research Resistance Role Scientist Series Signal Pathway Signal Transduction Somatic Cell Synthetic Peptide Libraries Tail Testing Time Training Transgenic Mice Translational Research Xenograft procedure anticancer research authority cancer cell career cell growth clinical application imaging modality in vitro Assay in vivo inhibitor/antagonist insight killings medical schools meetings men mouse model neoplastic cell novel outcome forecast personalized medicine prostate cancer cell prostate cancer cell line prostate carcinogenesis research study skills small molecular inhibitor targeted treatment tumor tumor growth tumor progression tumorigenesis upstream kinase

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to uncover the molecular mechanisms by which the newly identified Akt1 S477/T479 phosphorylation contributes to Akt activation and tumorigenesis, as well as to examine whether specifically inhibiting the upstream kinases for this phosphorylation event such as Cdk2/Cyclin A could block prostate tumor growth. My long-term career goals are to apply the insights of molecular and cellular biology to understand the physiological significance of deregulated protein kinase activation that is important in the development of human malignancies, and to search for proper drugable kinase targets. Akt is observed to be hyperactivated in human cancers, which is associated with the hormone-resistant phenotype and a poor prognosis. The significance of the PI3K/Akt pathway in prostate cancer has made it an attractive target for the development of small molecular inhibitors. However, the application of Akt inhibitors met difficulties in clinical trials due to induction of apoptosis in both cancer cells and normal somatic cells. Thus, to achieve specific eradication of cancer cells, it is critical to pinpoint the signaling pathways that distinguish caner cells from normal cells. Our preliminary data showed that another cancer hallmark, Cdk2/Cyclin A, could directly phosphorylate Akt1 at S477/T479 in a cell cycle dependent manner to govern Akt activation, providing specific growth advantages for cancer cells. Thus we are aiming to examine the molecular mechanisms through which Akt1-pS477/pT479 phosphorylation facilitates Akt activation and whether inhibiting its upstream activation kinase, Cdk2/Cyclin A could specifically kill cancer cells. In this proposal, I plan to: 1) Elucidate the molecular mechanisms underlying cell cycle-dependent Akt activation; 2) Examine the role of of Akt1 S477/T479 phosphorylation in prostate tumorigenesis; 3) Determine whether targeted inhibition of Akt tail phosphorylation suppresses prostate cancer development through suppressing Akt activation. This K99/R00 award will provide protected time for me to pursue the hypotheses of this proposal, obtain new skill sets to execute experiments and solve problems. In addition, the award will also allow me to focus my efforts on independently conducting basic and translational research, and to train future young scientists. Should I receive this award, I will pursue this research in Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, where authorities in the fields of PI3 kinase signaling and prostate cancer research locate. The outcome of the proposed studies will help elucidate the detailed molecular mechanisms for Akt1-pS477/pT479 mediated Akt activation, provide evidence toward the rationale for using specific Cdk2/Cyclin A pharmacological intervention in personalized medicine for human cancers and deliver initial animal experimental results to test whether specifically targeting Cdk2/Cyclin A could retard prostate cancer progression in vivo.

描述（由申请人提供）：本提案的目的是揭示新鉴定的 Akt1 S477/T479 磷酸化促进 Akt 激活和肿瘤发生的分子机制，以及检查是否特异性抑制该磷酸化事件的上游激酶例如 Cdk2/Cyclin A 可以阻止前列腺肿瘤的生长。我的长期职业目标是应用分子和细胞生物学的见解来了解蛋白激酶激活失调的生理意义（这在人类恶性肿瘤的发展中很重要），并寻找适当的可药物激酶靶点。据观察，Akt 在人类癌症中过度激活，这与激素抵抗表型和不良预后有关。 PI3K/Akt 通路在前列腺癌中的重要性使其成为小分子抑制剂开发的有吸引力的靶点。然而，Akt抑制剂的应用在临床试验中遇到了困难，因为它会诱导癌细胞和正常体细胞的凋亡。因此，为了实现特异性根除癌细胞，找出区分癌细胞和正常细胞的信号通路至关重要。我们的初步数据表明，另一个癌症标志 Cdk2/Cyclin A 可以以细胞周期依赖性方式直接磷酸化 S477/T479 位点的 Akt1，以控制 Akt 激活，从而为癌细胞提供特定的生长优势。因此，我们的目的是研究 Akt1-pS477/pT479 磷酸化促进 Akt 激活的分子机制，以及抑制其上游激活激酶 Cdk2/Cyclin A 是否可以特异性杀死癌细胞。在这个提案中，我计划：1）阐明细胞周期依赖性Akt激活的分子机制； 2）考察Akt1 S477/T479磷酸化在前列腺肿瘤发生中的作用； 3) 确定靶向抑制 Akt 尾部磷酸化是否可以通过抑制 Akt 激活来抑制前列腺癌的发展。这个 K99/R00 奖项将为我提供受保护的时间来追求该提案的假设，获得新的技能来执行实验和解决问题。此外，该奖项还将使我能够集中精力独立开展基础研究和转化研究，并培养未来的年轻科学家。如果我获得这个奖项，我将在贝斯以色列女执事医疗中心 (BIDMC) 和哈佛医学院继续这项研究，那里是 PI3 激酶信号传导和前列腺癌研究领域的权威机构。拟议研究的结果将有助于阐明 Akt1-pS477/pT479 介导的 Akt 激活的详细分子机制，为在人类癌症个性化医疗中使用特定 Cdk2/Cyclin A 药理学干预的基本原理提供证据，并将初步动物实验结果提供给测试特异性靶向 Cdk2/Cyclin A 是否可以在体内延缓前列腺癌进展。