CLINICAL STUDIES OF SIGNAL TRANSDUCTION INHIBITORS

描述：（申请人的描述） 调节的细胞信号传导在肿瘤细胞转化中是关键的， 增殖 新的抗癌剂中断不同的点， 细胞信号通路正在进入临床。 雷帕霉素是一种新的 靶向单一蛋白质mTOR的免疫抑制剂，其似乎 在以前未识别的信号转导途径中发挥作用， G1/S期细胞周期转换。 雷帕霉素具有抗增殖 在多种肿瘤细胞类型中的活性。 本申请利用雷帕霉素及其类似物作为焦点， 在临床发展治疗学方面发展事业。 申请人 建议：1. 利用雷帕霉素类似物作为模型， 抑制细胞内信号传导的抗癌剂的开发 途径。 a.具有生长抑制活性的雷帕霉素类似物将进入 临床试验不久。 抗增殖作用已经在细胞中观察到， 表达EGF和PDGF受体的类型。 然而，初步研究表明， 表明决定敏感性的关键生长因子 肿瘤细胞对雷帕霉素类似物的反应是IGF。 在这些临床研究中， 肿瘤敏感性对EGF、PDGF和IGF表达的依赖性将是 在肿瘤组织样本（免疫组织化学）和患者血清中检测 （血清免疫测定）。 B.靶蛋白mTOR的含量及其一种 肿瘤组织样本中的推定靶点p70 K将通过以下方法测定： 免疫印迹。 结果将与肿瘤反应相关， 雷帕霉素 C.由于这些药物主要是细胞抑制性的，因此组合 最初将利用克隆形成测定法在体外测试方案。 的 新的信号转导调节剂mTOR，这是这些的目标， 试剂通过ras非依赖性途径刺激细胞增殖。 因此 用于组合研究的候选药物将包括（I）其它细胞因子， 干扰ras途径的信号传导剂 抑制剂，和（ii）非循环的经典细胞毒性剂 如铂类似物。 2. 提高临床专业知识 通过参加生物统计学课程进行药物开发研究，阶段 I临床试验设计，参与药代动力学/药物代谢 分析，科学会议（戈登会议，AACR特别会议， EORTC-NCI新药研讨会）。

DESCRIPTION: (Applicant's Description) Regulated cell signaling is critical in neoplastic cell transformation and proliferation. Novel anticancer agents interrupting different points in cell signaling pathways are entering the clinic. Rapamycin is a novel immunosuppressive agent targeting a single protein mTOR, which appears to function in a previously unrecognized signal transduction pathway necessary for G1/S phase cell cycle transition. Rapamycin has anti-proliferative activity in a variety of tumor cell types. This application utilizes rapamycin and its analogues as a focus in developing a career in clinical developmental therapeutics. The applicant proposes to: 1. utilize the rapamycin analogues as a model for the development of anticancer agents inhibiting intracellular signaling pathways. a. Rapamycin analogues with growth inhibitory activity will enter clinical trials shortly. Anti-proliferative effects have been seen in cell types which express EGF and PDGF receptors. Preliminary studies, however, indicate that the critical growth factor determining the sensitivity of tumor cells to the rapamycin analogues is IGF. In these clinical studies, the dependence of tumor sensitivity on EGF, PDGF, and IGF expression will be tested in tumor tissue samples (immunohistochemistry) and patient serum (serum immunoassay). b. Content of the target protein mTOR and one of its putative targets p70K in tumor tissue samples will be assayed via immunoblotting. Results will be correlated with tumor response to rapamycin. c. Since these agents are predominantly cytostatic, combination regimens will be tested initially in vitro utilizing clonogenic assays. The novel signal transduction regulator mTOR, which is the target of these agents, stimulates cell proliferation via a ras-independent pathway. Thus candidate drugs for combination studies will include (I) other cell signaling agents interfering with the ras pathway such as the farnesylation inhibitors, and (ii) classical cytotoxic agents which are non-cycle dependent such as the platinum analogues. 2. improve expertise in clinical drug development research through attending courses in biostatistics, phase I clinical trial design, involvement in pharmacokinetic/drug metabolism analyses, scientific meetings (Gordon Conference, AACR special meetings, EORTC-NCI new drug symposia).