Exploiting TOR Signaling for Cancer Drug Discovery

利用 TOR 信号传导进行癌症药物发现

• 批准号: 7407359
• 负责人: JING HUANG
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7407359
• 关键词: Antineoplastic Agents; Area; Biochemical; Biological Assay; Cancer Control; Cell Line; Cells; Class; Collaborations; Communities; Complementary DNA; Diabetes Mellitus; Drug resistance; Enhancers; Eukaryota; Eukaryotic Cell; Gene Expression Profiling; Genomics; Goals; Growth; Heart Hypertrophy; Immune; Investigation; Learning; Light; Link; Malignant Neoplasms; Mammalian Cell; Medical; Methods; Mission; Modeling; Molecular; Molecular Target; Neurodegenerative Disorders; Other Genetics; Pathway interactions; Pharmaceutical Preparations; Property; Protein Binding; Protein Kinase; Proteins; Proteome; Proteomics; RNA Interference; Resistance; Saccharomyces cerevisiae; Saccharomycetales; Safety; Signal Transduction; Sirolimus; Specificity; Syndrome; Testing; Therapeutic Intervention; Treatment Efficacy; Yeasts; analog; cancer cell; cancer therapy; cell growth; chemical genetics; concept; drug development; drug discovery; fitness; high throughput screening; human disease; in vivo; inhibitor/antagonist; novel; novel strategies; prevent; research study; small molecule; success; tumor

DESCRIPTION (provided by applicant): The function of the TOR (target of rapamycin) protein kinase pathway is central to cell growth control in eukaryotes. Rapamycin and its analogs are under intense investigation for their potential in cancer therapies. The broad, long-term goals of this proposal are: (I) To better understand the molecular mechanisms of TOR signaling in cell growth control, (II) To elucidate the mechanisms of cellular sensitivity to rapamycin, and (III) To learn how TOR signaling properties can be exploited to advance the treatment for human diseases linked to this pathway. Towards these ends, we are developing a novel chemical-genetic and proteomic approach to rapidly and efficiently discover using the budding yeast, Saccharomyces cerevisiae, which is an established model to study TOR signaling, cell growth control, and cancer-related, conserved pathways. In preliminary studies, we have discovered two classes of novel small molecules that modify rapamycin's growth-inhibitory effects: the SMIRs (small molecule inhibitors of rapamycin) and the SMERs (small molecule enhancers of rapamycin). Our studies of the SMIRs have led to the discovery of new mechanisms in regulating TOR pathway activity. We will apply similar concepts and methods to study the SMERs, which we envision to be useful for a) enhancing rapamycin's therapeutic efficacy, b) treating rapamycin-insensitive tumors, and/or c) preventing the development of drug resistance to rapamycin, all of which are expected to have significant impact on TOR-targeted therapies. The hypothesis that will be tested is that perturbations of the TOR pathway create a set of distinct cellular states that can be selectively targeted to cause reduction (or loss) in fitness in cancer cells. Our specific Aims are: 1) to perform high- throughput screening to identify small molecules that are synthetic-lethal with perturbations of the TOR pathway, 2) to characterize the SMERs and test their activities in mammalian cells, and 3) to identify the protein targets for the SMERs and elucidate their mechanisms in TOR pathway modulation. Upon successful completion, the project will have demonstrated a new paradigm for cancer drug discovery, target identification, and mechanism studies in search of cures, which aligns closely with the missions of the NCI/NIH. The search for effective therapies for cancer presents a compelling challenge to the scientific and medical community. Our studies aim to combine two of the most powerful concepts in this area, namely molecularly targeted therapy and synthetic lethality, to achieve greatest specificity, efficacy, and safety in therapeutic intervention. We believe that our studies will shed new light on basic mechanisms of TOR signaling as well as TOR-targeted therapy. Furthermore, the methods that we develop and test here will be broadly applicable to the study of other cancer drugs, other pathways and other human diseases.

描述(由申请人提供)：TOR(雷帕霉素靶标)蛋白激酶途径的功能是真核生物细胞生长控制的核心。雷帕霉素及其类似物正因其在癌症治疗中的潜力而受到密切研究。这项建议的广泛和长期目标是：(I)更好地了解TOR信号在细胞生长控制中的分子机制，(Ii)阐明细胞对雷帕霉素敏感的机制，以及(Iii)了解如何利用TOR信号特性来推进与这一途径相关的人类疾病的治疗。为此，我们正在开发一种新的化学遗传学和蛋白质组学方法来快速有效地发现使用萌芽酵母酿酒酵母，这是一个建立的模型，以研究TOR信号，细胞生长控制，以及与癌症相关的保守途径。在初步研究中，我们发现了两类新的小分子来改变雷帕霉素的生长抑制作用：SMIR(雷帕霉素的小分子抑制剂)和SMERs(雷帕霉素的小分子增强剂)。我们对SMIR的研究发现了调控TOR途径活性的新机制。我们将使用类似的概念和方法来研究SMERs，我们预计这将有助于a)提高雷帕霉素的治疗效果，b)治疗雷帕霉素不敏感的肿瘤，和/或c)防止对雷帕霉素产生耐药性，所有这些都有望对TOR靶向治疗产生重大影响。将被测试的假设是，TOR途径的扰动产生了一组不同的细胞状态，可以选择性地针对这些状态来导致癌细胞适应性的降低(或丧失)。我们的具体目标是：1)进行高通量筛选，以识别在TOR途径扰动下合成致死的小分子；2)表征SMERs并测试其在哺乳动物细胞中的活性；3)识别SMERs的蛋白质靶标并阐明其在TOR途径调控中的作用机制。在成功完成后，该项目将展示一种新的癌症药物发现、目标识别和寻找治疗方法的机制研究的范例，这与NCI/NIH的任务密切一致。寻找有效的癌症治疗方法是科学界和医学界面临的一个紧迫挑战。我们的研究旨在结合这一领域最强大的两个概念，即分子靶向治疗和合成致命性，在治疗干预中实现最大的特异性、有效性和安全性。我们相信，我们的研究将为TOR信号转导的基本机制以及TOR靶向治疗提供新的线索。此外，我们在这里开发和测试的方法将广泛适用于其他抗癌药物、其他途径和其他人类疾病的研究。