Sapacitabine therapy to create synthetic lethality in DNA repair-deficient CLL

沙帕西他滨疗法可在 DNA 修复缺陷的 CLL 中产生合成致死率

• 批准号: 8519387
• 负责人: WILLIAM K PLUNKETT
• 金额: $ 30.82万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519387
• 关键词: 11q; 11q22; 11q22.3; ATM deficient; ATM function; ATM gene; Acute Myelocytic Leukemia; Affect; Alkylating Agents; Alleles; Antibody Therapy; Bioavailable; Biological Assay; Biological Models; Cell Line; Cell Survival; Cells; Chromosomes, Human, Pair 11; Clinical; Clinical Trials; Cyclophosphamide; DNA; DNA Damage; DNA Repair; DNA biosynthesis; DNA strand break; Deoxycytidine; Development; Disease; Disease Progression; Disease remission; Drug Formulations; Drug resistance; Excision Repair; Exhibits; Future; Genetic; Goals; In Vitro; In complete remission; Incidence; Investigation; Laboratories; Lesion; Location; Malignant Neoplasms; Modeling; Mutate; Mutation; Nonhomologous DNA End Joining; Nucleotides; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Prior Therapy; Process; Proliferating; Purine Nucleosides; Refractory; Relapse; Relative (related person); Residual state; Role; Safety; Sampling; Site; Specificity; Structure; Testing; Time; Translating; Treatment Failure; Work; analog; arm; base; design; ds-DNA; fludarabine; gene function; high risk; homologous recombination; improved; killings; leukemia; novel; nucleoside analog; public health relevance; recombinational repair; repaired; response; rituximab; success; tripolyphosphate

DESCRIPTION (provided by applicant): There has been remarkable progress in the treatment of CLL during the last decade. The introduction of fludarabine and other purine nucleoside analogs generated a significant improvement in responses relative to alkylating agents.1-3 Subsequently combinations of these two classes of agents, in particular fludarabine and cyclophosphamide, were proved superior to single agent fludarabine.4-6 Recently strategies to include antibody therapy, particularly with rituximab have given substantial increases in the complete response rate for CLL patients.4, 7-11 and an indication of increased overall survival in response to fludarabine-cytoxan-rituximab (FCR) therapy.12 Nevertheless, relapses remain problematic and development of drug resistance continues to be a major challenge in CLL treatment.11. Such drug resistance may in part be due to certain genetic alterations. A deletion at 11q22-23, the site of the ATM gene, occurs in half of relapsed/refractory patients. Mutation of the residual allele in approximately 50% of these patients inactivates homologous recombination (HR) repair of double strand breaks in CLL cells. Because Sapacitabine causes one-ended double strand breaks, cells that lack ATM are selectively sensitized. We hypothesize that the novel mechanism of action of Sapacitabine in CLL cells that lack ATM function, and are therefore are in repairing the lesion by homologous recombination, will create synthetic lethality and confer specificity of killing. We will conduct a clinical trial of Sapacitabine combined with cyclophosphamide and rituximab in relapsed/refractory patients with CLL who exhibit deletion 11q22-23 with the following specific aims: 1) test the hypothesis that CLL lacking ATM function (homologous recombination repair) will be selectively sensitized to Sapacitabine- containing therapy as indicated by a greater overall response rate and longer response duration; 2) identify CLL patients whose disease lacks ATM function, and analyze clinical response with respect to this parameter. Demonstrating efficacy in patients with deletion 11q22-23, lacking ATM function, would be a significant advance in treatment for this high-risk group of patients, and would validate ATM as a target for Sapacitabine- containing therapy in CLL, and 3) conduct investigations with CLL samples obtained from patients entered on the trial that will translate the findings in models systems to these primary CLL cells.

描述（由申请人提供）：在过去的十年里，CLL的治疗取得了显著的进展。氟达拉滨和其他嘌呤核苷类似物的引入与烷基化剂相比，显著改善了反应。1-3随后，这两类药物的联合用药，特别是氟达拉滨和环磷酰胺，被证明优于单药氟达拉滨。最近包括抗体治疗的策略，特别是利妥昔单抗，大大提高了CLL患者的完全缓解率。4,7 -11和氟达拉滨-环toxan-利妥昔单抗（FCR）治疗的总生存率增加的适应症然而，复发仍然是一个问题，耐药的发展仍然是CLL治疗的主要挑战。这种耐药性可能部分是由于某些基因的改变。ATM基因11q22-23位点的缺失发生在一半的复发/难治性患者中。在这些患者中，大约50%的残留等位基因突变使CLL细胞双链断裂的同源重组（HR）修复失活。由于萨帕他滨导致单端双链断裂，缺乏ATM的细胞被选择性致敏。我们假设萨帕他滨在缺乏ATM功能的CLL细胞中的新作用机制，因此通过同源重组修复病变，将产生合成致死性并赋予特异性杀伤。我们将在11q22-23缺失的CLL复发/难治患者中开展沙帕他滨联合环磷酰胺和美罗华的临床试验，具体目的如下：1)验证缺乏ATM功能（同源重组修复）的CLL对沙帕他滨选择性致敏的假设，其总体反应率更高，反应持续时间更长；2)识别疾病缺乏ATM功能的CLL患者，并根据该参数分析临床反应。证明对缺失11q22-23、缺乏ATM功能的患者有效，将是治疗这一高危患者的重大进展，并将验证ATM作为含沙帕他滨CLL治疗的靶点。3)对从进入试验的患者获得的CLL样本进行调查，这将翻译