Mechanism-Based Pharmacologic Intervention

基于机制的药物干预

基本信息

批准号：
8235346
负责人：
WILLIAM K PLUNKETT
金额：
$ 15.16万
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：
2011
资助国家：
美国
起止时间：
2011-12-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235346
关键词：
11q22 ATM function ATM gene Alkylating Agents Alleles Antibody Therapy Apoptotic Biological Assay Biological Models Biology Bone Marrow Cell Survival Cells Cessation of life Chronic Lymphocytic Leukemia Clinical Clinical Trials Combined Modality Therapy Cyclophosphamide Cytotoxic Chemotherapy DNA lesion Development Disease Double Strand Break Repair Drug resistance Elements Environment Exhibits Functional disorder Gene Targeting Generations Genetic Genetic Transcription Glutathione Goals Histone Deacetylase Inhibitor Histones In Vitro In complete remission Instruction Intervention Investigation Lesion Mediating MicroRNAs Mutate Mutation Neoadjuvant Therapy Outcome Oxidative Stress Patients Process Purine Nucleosides Reactive Oxygen Species Reduced Glutathione Refractory Relapse Relative (related person)Research Residual state Resistance Site Specificity Stromal Cells Testing Therapeutic Time Tissues Tumor Suppressor Proteins base chemotherapy fludarabine high risk homologous recombination improved in vivo killings leukemia loss of function novel novel strategies novel therapeutic intervention nucleoside analog patient population prevent pro-apoptotic protein repaired resistance mechanism response rituximab small molecule success therapeutic development therapy resistant ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY (See instructions): While development of new therapeutic approaches have contributed to the increase in the complete remission rate for CLL patients, relapses and resistance to re-treatment remain a significant problem. Nevertheless, changes that occur in the biology of CLL upon relapse from front-line therapies provide clues to resistance mechanisms that prevent prolonged complete responses. Our overall strategy is to employ three novel approaches that are each directed at an aspect of the pathophysiology of CLL and the mechanisms associated with resistance. First, a deletion at 11q22-23, the site of the ATM gene, occurs in half of relapsed/refractory patients. Mutation of the residual allele (-50%) inactivates homologous recombinafion (HR) repair of double strand breaks. Because Sapacitabine causes one-ended double strand breaks, cells that lack ATM are selectively sensitized. We will develop assays to identify patients who's CLL lacks ATM function, and initiate a clinical trial of Sapacitabine therapy to test the hypothesis that their disease will be selecfively sensitized. Second, studies in model systems demonstrate that loss of p53 function is a resistance mechanism to cytotoxic therapy. Neariy half of relapsed refractory patients lack p53 funcfion. We postulate that expression of the epigenetically silenced p73 will serve in place of p53 to activate expression of pro-apoptotic proteins. This will be validated in model systems and tested in a clinical trial. Third, a novel mechanism by which the microenvironment sustains CLL cells and increases resistance to chemotherapy appears to act by providing precursors for glutathione. This sustains CLL by neutralizing the destructive action of reactive oxygen species that are innately over-expressed by CLL. By using a small molecule to reduce glutathione we will test this hypothesis to sensitize CLL cells in vitro and in vivo. These investigations will provide mechanism-based rationales for development of combination therapies.

项目摘要（参见说明）：虽然新治疗方法的开发有助于提高 CLL 患者的完全缓解率，但复发和对再治疗的抵抗仍然是一个重大问题。然而，一线疗法复发后 CLL 生物学发生的变化为阻止长期完全缓解的耐药机制提供了线索。我们的总体策略是采用三种新颖的方法，每种方法都针对 CLL 病理生理学的一个方面以及与耐药性相关的机制。首先，ATM 基因位点 11q22-23 发生缺失一半的复发/难治性患者。残留等位基因（-50%）的突变使双链断裂的同源重组（HR）修复失活。由于 Sapacitabine 会导致单端双链断裂，因此缺乏 ATM 的细胞会被选择性地致敏。我们将开发检测方法来识别 CLL 缺乏 ATM 功能的患者，并启动沙帕西他滨治疗的临床试验，以测试他们的疾病将选择性致敏的假设。其次，模型系统的研究表明 p53 的丢失功能是对细胞毒治疗的抵抗机制。近一半的复发难治性患者缺乏 p53 功能。我们假设表观遗传沉默的 p73 的表达将代替 p53 来激活促凋亡蛋白的表达。这将在模型系统中得到验证并在临床试验中进行测试。第三，微环境维持CLL细胞并增加抵抗力的新机制化疗似乎通过提供谷胱甘肽前体来发挥作用。这通过中和 CLL 固有过度表达的活性氧的破坏作用来维持 CLL。通过使用小分子来还原谷胱甘肽，我们将测试这一假设，以在体外和体内使 CLL 细胞变得敏感。这些研究将为联合疗法的开发提供基于机制的原理。