Pharmacologic Inhibitors of Cellular Kinases and Signal Transduction

项目总结（见说明）： 项目6：细胞激酶和信号转导的药理学抑制剂 慢性淋巴细胞白血病（CLL）目前最初采用化学免疫疗法（CIT）治疗。尽管 由于这一进展，几乎所有接受CIT的患者都会复发并最终死于疾病。最近 确定B细胞转化生物学的核心目标提供了一个机会， 在CLL中的治疗范例，如在慢性髓性白血病中所做的那样。在这方面，我们 研究靶向细胞周期蛋白依赖性激酶（CDK; flavopihdol和 SCH 727965）和磷酸肌醇3-激酶δ（PlSK-δ; CAL-101）。Flavopiridol，SCH 727965，和 CAL-101各自在复发性和难治性CLL患者中表现出显著的临床活性。 这些药物杀死CLL细胞和干扰微环境的机制 保护以及产生抗药性的途径尚不确定。通过详细的机械 审讯，我们将确认和扩大我们强大的预审数据。与此同时，我们还将执行 伴随使用每种药剂的CRC I/II期试验的转化研究。具体目标1：执行 Flavopiridol和SCH 727965的机制研究，以研究：a）ER应激对细胞死亡的贡献 B）自噬对CDK抑制剂耐药性的贡献; c）自噬对CDK抑制剂耐药性的影响。 微环境对慢性淋巴细胞白血病细胞CDK抑制剂耐药的影响及治疗策略 用新的靶向药物克服这些问题，和d）药效学研究的性能， 在CRC中完成和计划的CDK抑制剂临床试验。具体目标2：询问PI 3 K-delta 途径，特别关注：1）鉴定CAL-101促进直接 对CLL细胞的细胞毒性; 2）CAL-101拮抗的外部信号在CLL细胞中的相关性。 3）TCLI中PI 3 K-δ抑制剂的临床前测试 CLL小鼠模型，以进一步验证与该药剂的最佳组合研究，以及4） 与计划在CRC中进行的CAL-101临床试验一致的药效学研究。

PROJECT SUMMARY (See instructions): PROJECT 6 : Pharmacologic Inhibitors of Cellular Kinases and Signal Transduction Chronic lymphocytic leukemia (CLL) is currently initially treated with chemoimmunotherapy (CIT). Despite this advance, virtually all patients receiving CIT relapse and ultimately die from their disease. Recent identification of targets central to the biology of B-cell transformation provides an opportunity to set a new treatment paradigm in CLL, as has been done in chronic myeloid leukemia. In this regard, we are investigating clinically active kinase inhibitors that target cyclin-dependent kinases (CDK; flavopihdol and SCH727965) and phosphoinositide 3-kinase delta (PlSK-delta; CAL-101). Flavopiridol, SCH727965, and CAL-101 each have demonstrated signficant clinical activity in patients with relapsed and refractory CLL. The mechanisms by which each ofthese agents kill CLL cells and interfere with microenvironmental protection, as well as pathways by which resistance develops, are uncertain. Through detailed mechanistic interrogation we will confirm and extend our strong prelimitiary data. In conjunction, we will also perform translational studies accompanying CRC phase l/ll trials with each agent. Specific Aim 1: To perform mechanistic studies of flavopiridol and SCH727965 to study: a) The contribution of ER stress to cell death promoted by these agents, b) The contribution of autophagy to CDK inhibitor drug resistance; c) The influence of microenvironment on promoting resistance to CDK inhibitors in CLL cells and strategies to overcome these with novel targeted agents, and d) performance of pharmacodynamic studies with completed and planned CDK inhibitor clinical trials in the CRC. Specific Aim 2: To interrogate the PI3K-delta pathway with particular focus on: 1) Identification ofthe mechanism by which CAL-101 promotes direct cytotoxicity toward CLL cells; 2) Relevance of external signals antagonized by CAL-101 in the microenvironment to the survival of CLL cells; 3) Pre-clinical testing of PI3K-delta inhibitors in the TCLI mouse model of CLL to further validate optimal combination studies with this agent, and 4) performance of pharmacodynamic studies in concert with the planned CAL-101 clinical trials in the CRC.