Development of Mechanism-Based Stratgies for CLL Therapy

开发基于机制的 CLL 治疗策略

基本信息

批准号：
8068813
负责人：
WILLIAM K PLUNKETT
金额：
$ 27.03万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8068813
关键词：
8-chloroadenosine Address Adenosine Alkylating Agents Animal Model Antineoplastic Agents Apoptotic BIRC4 gene Biochemical Biological Models CDK9 Protein Kinase Cell Death Cell Survival Cells Characteristics Cladribine Clinic Clinical Clinical Trials Clofarabine Collaborations Combined Modality Therapy Cyclophosphamide Cytotoxic agent DNA Damage DNA Repair DNA Repair Inhibition Development Drug Kinetics Energy Supply Evaluation Excision Excision Repair Genetic Transcription Goals In Vitro Investigation Knowledge Laboratories Lymphocyte Metabolism Mitochondria Molecular Biology Molecular Target Nelarabine New Agents Normal Cell Oncogenes Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Preparation Process Prodrugs Property Proteins Reducing Agents Resistance Ribonucleosides Ribonucleotides Sampling Schedule Signal Pathway TP53 gene Testing Therapeutic Therapeutic Agents Time Treatment Protocols Vidarabine analog anti-cancer therapeutic anticancer activity base cell killing clinical efficacy cyclin T1 cytotoxic design flavopiridol fludarabine improved in vivo inhibitor/antagonist killings knowledge base novel novel therapeutics nucleoside analog nucleotide analog phase 1 study programs repaired research clinical testing response

项目摘要

The goals of this project are to develop in the laboratory, using model systems and primary CLL cells in vitro an understanding of the mechanisms of action of anticancer agents acting alone and in mechanism-based combinations. This knowledge base will provide rationales for the design and evaluation of clinical trials that will test hypotheses regarding the actions and interactions of these agents in CLL cells in patients during therapy. Thus, the central hypothesis we will test is that knowledge derived from an understanding of the metabolism, mechanisms of action, and the interactions of new anticancer therapeutics can be used to design and evaluate novel therapeutic regimens for the treatment of patients with CLL. To achieve these goals, we will address the following questions: 1. Do nucleoside analogs with novel actions provide pharmacological and clinical advantages over fludarabine for the treatment of B-CLL? Our focus here will be on the new nucleoside analog, clofarabine which has pharmacologic properties different from fludarabine. 2. Can strategies to reduce survival proteins selectively kill CLL cells? We are developing 8-chloro-adenosine ribonucleotide analog that reduces cellular bioenergy and blocks transcription. Also, we will evaluate the transcription-directed actions of flavopiridol. The actions of each of these agents decreases anti-apoptotic proteins in CLL cells. 3. Will mechanism-based combinations of cytotoxic agents improve outcome in CLL patients? The cellular responses to inhibition of excision DNA repair processes will be investigated in CLL cells, and extended to new DNA damaging agents and drugs that inhibit DNA repair. 4. Can orsaponin, a synthetic natural compound with potent anticancer activity and unique mechanism of action, be used as a novel agent for treatment of CLL? The action mechanism(s) of this novel agent that selectively kills CLL cells independent of p53 status will be investigated in preparation for clinical development. Interactions with other projects in this program will strengthen our investigations.

该项目的目标是在实验室中使用模型系统和体外原代 CLL 细胞进行开发了解单独作用和基于机制的抗癌药物的作用机制组合。该知识库将为临床试验的设计和评估提供基本原理，将测试有关这些药物在患者 CLL 细胞中的作用和相互作用的假设治疗。因此，我们要检验的中心假设是，知识源自对事物的理解。新抗癌疗法的代谢、作用机制和相互作用可用于设计和评估治疗 CLL 患者的新治疗方案。为了实现这些为了实现目标，我们将解决以下问题： 1. 具有新颖作用的核苷类似物是否提供与氟达拉滨治疗 B-CLL 相比，其药理学和临床优势如何？我们这里的重点将是新型核苷类似物氯法拉滨具有与氟达拉滨不同的药理特性。 2. 减少存活蛋白的策略能否选择性杀死 CLL 细胞？我们正在开发8-氯腺苷核糖核苷酸类似物，可减少细胞生物能量并阻止转录。此外，我们还将评估黄吡醇的转录指导作用。这些药物中的每一种的作用都会降低抗凋亡作用 CLL 细胞中的蛋白质。 3. 基于机制的细胞毒性药物组合能否改善 CLL 的预后患者？将在 CLL 中研究细胞对抑制 DNA 切除修复过程的反应细胞，并扩展到新的 DNA 损伤剂和抑制 DNA 修复的药物。 4. 可以奥皂甙，a 合成的天然化合物，具有有效的抗癌活性和独特的作用机制，可用作治疗 CLL 的新药？这种选择性杀死 CLL 的新型药物的作用机制将研究独立于 p53 状态的细胞，为临床开发做准备。互动该计划中的其他项目将加强我们的调查。