Mechanism-Based Pharmacologic Intervention

基于机制的药物干预

• 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
• 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

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.

项目总结(见说明)： 虽然新的治疗方法的发展有助于提高慢性粒细胞白血病患者的完全缓解率，但复发和对再次治疗的抵抗仍然是一个重要的问题。 然而，从一线治疗中复发后，CLL生物学上发生的变化为防止长期完全反应的耐药机制提供了线索。我们的总体策略是采用三种新的方法，每种方法都针对CLL的病理生理学和与耐药相关的机制的一个方面。首先，ATM基因11q22-23处的缺失发生在 一半的复发/难治性患者。残留等位基因突变(-50%)使双链断裂的同源重组(HR)修复失活。由于沙巴他滨导致单端双链断裂，缺乏ATM的细胞被选择性地敏化。我们将开发检测方法来识别缺乏ATM功能的CLL患者，并启动沙巴他滨治疗的临床试验，以测试他们的疾病将被选择性致敏的假设。其次，在模型系统中的研究表明，P53的丢失 功能是抵抗细胞毒治疗的一种机制。近半数复发难治性患者缺乏P53功能。我们推测，表观遗传沉默的p73的表达将取代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，微环境支持CLL细胞并增加抵抗力的新机制 化疗似乎是通过提供谷胱甘肽的前体起作用的。这通过中和CLL天生过度表达的活性氧物种的破坏性作用来维持CLL。通过使用小分子来还原谷胱甘肽，我们将在体外和体内测试这一假说来敏化CLL细胞。这些研究将为联合疗法的发展提供基于机制的理论基础。