Targeting mTOR for Cancer Therapy

靶向 mTOR 进行癌症治疗

• 批准号: 6856714
• 负责人: FUNDA MERIC-BERNSTAM
• 金额: $ 24.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856714
• 关键词: DNA replication; antineoplastics; athymic mouse; bioimaging /biomedical imaging; biomarker; breast neoplasms; carbohydrate transport; cell growth regulation; clinical research; cyclins; enzyme inhibitors; gene expression; genetic regulation; glucose; human genetic material tag; human tissue; neoplasm /cancer; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; phosphorylation; positron emission tomography; prognosis; prostate neoplasms; protein structure function; serine threonine protein kinase; sirolimus

DESCRIPTION (provided by applicant): Serine/threonine kinase mTOR (mammalian target of rapamycin) is a central regulator of cell growth and proliferation that modulates the transcription and translation of critical cell cycle regulatory molecules. Rapamycin and its analogues are in clinical trials, but have induced clinical responses in only a subgroup of patients. Therefore, there is a pressing need to identify biomarkers that can predict and monitor treatment response. We hypothesize that rapamycin modulates breast cancer biology by altering the expression of specific genes encoding for critical cell cycle and survival molecules. These gene products can be used to monitor response, and to determine which tumors will have significant growth inhibition. In specific Aim 1, we will determine the effect of rapamycin on the transcriptional, translational, and proteomic profile, and identify changes that occur in rapamycin-sensitive but not in rapamycin-resistant cells. We will determine the role of rapamycin-regulated genes in growth inhibition mediated by rapamycin. Then we will determine the effect of rapamycin analogue CCI-779 on the protein levels of selected targets in breast and prostate cancer patients treated with preoperative CCI-779. In Aim 2, we will evaluate cyclin D1 and BAG-1 as pharmacodynamic markers of response. We will determine the mechanism of rapamycin-mediated cyclin D1 and BAG-1 downregulation, and their role in growth-inhibition. In Aim 3, we will determine rapamycin's effect on DNA synthesis, protein synthesis, and glucose uptake in vivo by positron emission tomography and determine whether these studies may be early predictors of response. In Aim 4, we will determine whether mTOR activity predicts chemoresistance in breast cancer patients treated with preoperative chemotherapy. In addition, we will determine the mechanism of rapamycin-mediated enhancement of chemotherapy-induced cytotoxicity. With this study, we not only expect to identify pharmacodynamic markers of response for mTOR inhibitors but also to significantly enhance our understanding of mTOR inhibitors' mechanism of action.

描述（由申请人提供）：丝氨酸/苏氨酸激酶MTOR（雷帕霉素的哺乳动物靶标）是细胞生长和增殖的中心调节剂，可调节关键细胞周期调节分子的转录和翻译。 雷帕霉素及其类似物正在临床试验中，但仅在患者亚组中引起临床反应。因此，迫切需要识别可以预测和监测治疗反应的生物标志物。我们假设雷帕霉素通过改变针对关键细胞周期和存活分子的特定基因的表达来调节乳腺癌生物学。这些基因产物可用于监测反应，并确定哪些肿瘤将具有明显的生长抑制作用。在特定的目标1中，我们将确定雷帕霉素对转录，翻译和蛋白质组谱的影响，并确定对雷帕霉素敏感但不抗雷帕霉素耐药细胞中发生的变化。我们将确定雷帕霉素调节的基因在雷帕霉素介导的生长抑制中的作用。然后，我们将确定雷帕霉素类似物CCI-779对术前CCI-779治疗的乳腺癌和前列腺癌患者中选定靶标的蛋白质水平的影响。在AIM 2中，我们将评估细胞周期蛋白D1和BAG-1作为反应的药效标记。我们将确定雷帕霉素介导的细胞周期蛋白D1和BAG-1下调的机制，以及它们在抑制生长抑制中的作用。在AIM 3中，我们将通过正电子发射断层扫描中确定雷帕霉素对体内DNA合成，蛋白质合成和葡萄糖摄取的影响，并确定这些研究是否可能是反应的早期预测指标。在AIM 4中，我们将确定MTOR活性是否可以预测接受术前化学疗法治疗的乳腺癌患者的化学抗性。此外，我们将确定雷帕霉素介导的化学疗法诱导的细胞毒性增强的机制。通过这项研究，我们不仅希望鉴定MTOR抑制剂的反应的药效标记，而且还可以显着增强我们对MTOR抑制剂作用机理的理解。