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: 8373423
• 负责人: WILLIAM K PLUNKETT
• 金额: $ 32.79万
• 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/8373423
• 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; 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. PUBLIC HEALTH RELEVANCE: Patients with CLL who have leukemia cells with deletion of the long arm of chromosome 11 (11q), the location of the ATM gene, are high-risk for rapid disease progression, short remission duration, and short overall survival. The function of ATM is critical to repairing breaks in DNA and is frequently lost in this group of patients. This applicaton proposes to treat these patients with Sapacitabine, a drug that causes DNA strand breaks, with the view that the leukemia cells that lack ATM function will be specifically affected, resulting in improved clinical responses and remission rate.

描述（由申请人提供）：在过去十年中，CLL的治疗取得了显著进展。氟达拉滨和其他嘌呤核苷类似物的引入相对于烷化剂产生了显著的反应改善。1 -3随后，这两类药物的组合，特别是氟达拉滨和环磷酰胺，被证明上级单药氟达拉滨。4 -6最近的策略包括抗体治疗，特别是利妥昔单抗的治疗显著提高了CLL患者的完全缓解率。4，7-11和对氟达拉滨-环磷酰胺-利妥昔单抗（FCR）治疗应答的总存活率增加的指示。12然而，复发仍然是个问题，并且耐药性的发展仍然是CLL治疗中的主要挑战。这种耐药性可能部分是由于某些遗传改变。ATM基因的11 q22 -23位点缺失发生在一半的复发/难治性患者中。这些患者中约50%的残余等位基因突变使CLL细胞中双链断裂的同源重组（HR）修复失活。因为Sapacitabine导致单端双链断裂，所以缺乏ATM的细胞被选择性地致敏。我们假设，沙帕他滨在缺乏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杀伤特异性。我们将进行一项沙帕他滨联合环磷酰胺和利妥昔单抗治疗复发/难治性CLL患者的临床试验，这些患者表现出11 q22 -23缺失，具体目的如下：1）检验缺乏ATM功能的CLL（同源重组修复）将选择性地对含沙帕他滨的疗法敏感，如更大的总体响应率和更长的响应持续时间所指示的; 2）鉴定疾病缺乏ATM功能的CLL患者，并分析关于该参数的临床反应。在缺失11 q22 -23、缺乏ATM功能的患者中证明疗效将是治疗该高危患者组的显著进步，并且将验证ATM作为CLL中含沙帕他滨疗法的靶点，以及3）用从进入试验的患者获得的CLL样品进行研究，其将转化为对患者的治疗。 这些主要CLL细胞的模型系统中的发现。 公共卫生关系：CLL患者的白血病细胞缺失11号染色体长臂（11 q），ATM基因的位置，是疾病快速进展，缓解持续时间短，总生存期短的高风险。ATM的功能对于修复DNA断裂至关重要，并且在这组患者中经常丢失。该申请提出用Sapacitabine治疗这些患者，Sapacitabine是一种引起DNA链断裂的药物，其观点是缺乏ATM功能的白血病细胞将受到特异性影响，导致 改善临床反应和缓解率。