Targeting mTOR for Cancer Therapy

描述(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央调节因子，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进行临床试验，但只在一小部分患者中诱导了临床反应。因此，迫切需要确定能够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编码关键细胞周期和生存分子的特定基因的表达来调节乳腺癌的生物学。这些基因产物可用于监测反应，并确定哪些肿瘤将具有显著的生长抑制作用。在特定的目标1中，我们将确定雷帕霉素对转录、翻译和蛋白质组学的影响，并确定在雷帕霉素敏感但不耐药的细胞中发生的变化。我们将确定雷帕霉素调节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对术前接受CCI-779治疗的乳腺癌和前列腺癌患者选定靶点蛋白水平的影响。在目标2中，我们将评估细胞周期蛋白D1和BAG-1作为疗效的药效学标志物。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，以及它们在生长抑制中的作用。在目标3中，我们将通过正电子发射断层扫描来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因素。在目标4中，我们将确定mTOR活性是否可以预测接受术前化疗的乳腺癌患者的化疗耐药性。此外，我们还将确定雷帕霉素介导的增强化疗细胞毒作用的机制。通过这项研究，我们不仅希望确定mTOR抑制剂反应的药效学标志物，而且还将显著增强我们对mTOR抑制剂作用机制的理解。

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.